Journal articles on the topic 'Modified progressive profiling'
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Kang, Wenyu, Jun Niimi, Richard A. Muhlack, Paul A. Smith, and Susan E. P. Bastian. "Dynamic characterization of wine astringency profiles using modified progressive profiling." Food Research International 120 (June 2019): 244–54. http://dx.doi.org/10.1016/j.foodres.2019.02.041.
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Boekhoff, Henning, Laura Hendricks, Elena Cairo, Andrea Bauer, Mari Hambardzumyan, Markus W. Büchler, Silvia Calderazzo, et al. "Abstract A035: Profiling of circulating autoreactive antibodies in some 1200 patients with pancreatic ductal adenocarcinoma and progressive precursor lesions." Cancer Research 82, no. 22_Supplement (November 15, 2022): A035. http://dx.doi.org/10.1158/1538-7445.panca22-a035.
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Abstract Tumor-associated autoreactive antibodies could represent a moderately sensitive but highly specific type of biomarker. While autoantibodies in the blood of patients with pancreatic cancer have been reported, the consensus among studies is low and data validation is lacking. We profiled the abundance of circulating autoantibodies in patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-step approach. For this purpose, microarrays with in situ expressed proteins were produced that contained 3060 non-mutated human proteins; one emphasis was on cell surface proteins. The microarrays were utilized for autoantibody screening of sera collected from patients of PDAC stages I, IIA, IIB/III and IV. In addition, samples were studied that represented the different grades of the precursor lesion intraductal pupillary mucinous neoplasm (IPMN) – low-grade, high-grade dysplasia and IPMN with associated carcinoma. Third, sera from patients diseased with the PDAC risk factor chronic pancreatitis (CP) as well as healthy donors served as control groups. The analysis revealed a significant increase in the overall proportion of immunoreactive proteins in late grades of IPMN and stages of PDAC; within each group, some sera displayed higher reactivity than others. The screening phase led to the identification of about 100 proteins, which showed a relatively high immunoreactivity associated with PDAC in comparison to an age- and sex-matched healthy control group. The characteristics of PDAC-associated autoantibodies were confirmed for the 100 proteins by analyzing sera from a total of 1200 PDAC, IPMN and CP patients as well as healthy donors. The patient groups were age- and sex-matched among each other. This confirmation phase validated the PDAC-related immunoreactivity of 17 proteins, showing high specificity of samples from PDAC patients in comparison to the healthy control group but low sensitivity of less than 10%. The clinically defined PDAC stages displayed different autoantibody profiles. However, no stage-related autoantibodies could be identified. Further, these PDAC-related antigens were also immunoreactive in smaller proportions of CP and IPMN patients, demonstrating the biological relation between PDAC and its precursors CP and IPMN. The majority of the other antigens showed a high immunoreactivity without correlation of autoantibody abundance and PDAC diagnosis, highlighting the importance of validation in large cohorts. The presence of autoantibodies specific for the 17 identified PDAC-related proteins is currently technically cross-validated by Luminex multiplex serology. In conclusion, the study has identified novel PDAC-related autoantibodies towards non-modified human proteins. While the specificity of some detected autoantibodies was high, the low sensitivity and the immunoreactivity of related precursor lesions make the definition of a broad applicable biomarker panel unlikely or too complex. However, the antigens that are specific for PDAC indicate target molecules, which could offer new therapeutic options in a personalized approach. Citation Format: Henning Boekhoff, Laura Hendricks, Elena Cairo, Andrea Bauer, Mari Hambardzumyan, Markus W. Büchler, Silvia Calderazzo, Vivienn Weru, Anette Kopp-Schneider, Hermann Brenner, Thilo Hackert, Oliver Strobel, Tim Waterboer, Nathalia Giese, Joerg D. Hoheisel. Profiling of circulating autoreactive antibodies in some 1200 patients with pancreatic ductal adenocarcinoma and progressive precursor lesions [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A035.
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Manzi, Vincenzo, Carlo Castagna, Elvira Padua, Mauro Lombardo, Stefano D'Ottavio, Michele Massaro, Maurizio Volterrani, and Ferdinando Iellamo. "Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 6 (June 2009): H1733—H1740. http://dx.doi.org/10.1152/ajpheart.00054.2009.
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In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMPi) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMPi steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model ( r2 ranged from 0.90 to 0.99; P < 0.001). Variance, high-frequency oscillations of HR variability (HRV), and baroreflex sensitivity resembled a bell-shaped curve with a minimum at the highest TRIMPi, whereas low-frequency oscillations of HR and systolic arterial pressure variability and the low frequency (LF)-to-high frequency ratio resembled an U-shaped curve with a maximum at the highest TRIMPi. The LF component of HRV assessed at the last recording session was significantly and inversely correlated to the time needed to complete the nearing marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population.
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Wang, Xuehai, Deanne Gracias, Michael Nissen, Elizabeth Chavez, Gabriela Cristina Segat, Manabu Kusakabe, Guillermo Simkin, et al. "Single-Cell Profiling Reveals Distinct Tumor Subtypes and Their Associated T-Cell Environments in Follicular Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 1577. http://dx.doi.org/10.1182/blood-2018-99-114182.
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Abstract Follicular lymphoma (FL) is an indolent, but incurable malignancy as most patients eventually experience progressive disease. We hypothesized that clonal heterogeneity and patient-specific immune responses would contribute to variable clinical outcomes and that understanding the complexity of the entire tumor "ecosystem" would allow us to better match patients with specific types of tumor- and immune-targeted therapies. In this study, we performed 38-dimensional single-cell phenotyping by mass cytometry (CyTOF) to simultaneously characterize both the substructure of malignant B cell populations as well as the T cell microenvironment in a cohort of 77 diagnostic patient FL biopsies and 35 benign reactive LN (rLN) biopsies. We first applied the t-distributed Stochastic Neighbour Embedding (t-SNE) algorithm to explore intra- and inter- tumoral heterogeneity among malignant B cell populations. t-SNE mapping of individual samples showed that more than a third of FL samples contain at least two phenotypically distinct tumor subpopulations, supporting the notion of multi-clonal tumor architectures presumably due to ongoing clonal evolution. Batched analysis combining all 77 FL cases together with 35 rLN samples revealed two distinct tumor subtypes comprising about 25% (type "A") and 10% (type "B") of total FL samples, respectively, with individual tumors within each subtype showing highly similar and partially overlapping phenotypes. Mapping the same data using Uniform Manifold Approximation and Projection (UMAP), a dimensional reduction algorithm similar to t-SNE but preserves global structure more accurately, revealed that type A tumors localized in close proximity to normal germinal center (GC) B cells, thus fulfilling conventional expectations as to the histogenesis of FL. In contrast, type B tumors localized more closely to pre-GC B cells, implying the existence of an alternate histogenic path in FL. Importantly, we also performed single-cell RNA-Seq on a subset of FL cases which independently confirmed the type A vs type B distinction in whole transcriptomic space. We next analyzed matching T cell data using a modified Statistical Scaffold algorithm in order to place distinct subsets in context with conventionally defined normal T cell populations. Clustering analysis using multi-layer phenograph performed on T cells from all FL and rLN samples combined yielded hundreds of small, but phenotypically distinct populations that were then annotated according to the nearest conventionally defined T cell subset. These imputed designations were used as features to perform hierarchical clustering of samples which revealed 3 major clusters. Cluster1 was characterized by mostly naive T cell populations and contained the majority of rLN samples. Cluster2 was characterized by more differentiated effector T cell populations and was dominated by FL samples. Samples within Cluster2 could be further divided into Tfh, Treg and Th1-rich subgroups. Cluster3 was characterized by a diverse T cell environment including naive, memory and differentiated effector subsets and contained a mixture of rLN and FL samples. Integrative analysis correlating B- and T- cell features revealed type B FL tumors were associated with a Tfh-rich immune landscape. Taken together, these data reveal pervasive phenotypic heterogeneity in both malignant and immune cell compartments of patient FL samples and suggest that defining tumoral subtypes as well as the status of the local immune response within individual samples will support more refined diagnostic classification and highlight functional interactions most amenable to therapeutic targeting. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Roche: Consultancy.
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Gupta, Sameer, Jeetendra Paryani, Arun Chaturvedi, Vijay Kumar, and Naseem Akhtar. "Triple negative breast cancer: An Indian problem— Experience from a tertiary care oncology centre." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12583-e12583. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12583.
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e12583 Background: Breast cancer is a heterogeneous disease with distinct biological subtypes as determined by gene expression profiling studies. Breast cancer is most common cancer in Indian females and is believed to be biologically different from west, notably in terms of high prevalence of Triple negative subtype (TNBC). Reliable data on clinical and epidemiological profile of TNBC in Indian population is scarce. Aim of this study was to analyze the epidemiological and clinical profile of TNBCs Methods: Data of 355 patients of breast cancer registered in our department between 2013 and 2015 and followed up until December 2016 was collected and reviewed for epidemiological and clinical features Results: Of total 355 patients analysed, TNBC group was most common (n = 152) (43%) followed by Luminal A (25%). Median age at disease presentation in TNBC was 42.4 years compared to overall age of 45.3 years (24–73 years). In TNBC subgroup, 48% patients presented in locally advanced and 15% in metastatic stage, more commonly in pre-menopausal patients. Overall 268 (76%) patients underwent surgery with Modified radical mastectomy being preferred surgical option (86%), followed by adjuvant chemotherapy. TNBC subgroup demonstrated low response rate to neoadjuvant chemotherapy with only 9% of patients having complete response and 25% patients having progressive disease. Median followup was 34 months (6 50 months). Of the total recurrences (n = 19), nearly 2/3rd (n = 13) were documented in TNBC subgroup. Disease free survival (DFS) of TNBC subgroup was lower than of other luminal subtypes (p = .043) Conclusions: TNBC was the most common breast cancer subtype (43%) in Indian population which is nearly twice the rate reported in Western countries. This finding has significant clinical relevance as it may contribute to poor outcomes in Indian patients. Our study also corraborated this fact with higher prevalence of premenopausal breast cancer, poor response to neoadjuvant chemotherapy, high recurrence rates and decreased disease free survival. Additional research is needed to understand the determinants of TNBC in India as it is a prognostic group with aggressive behaviour that commonly lack the benefit of any specific targeted therapy
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Furini, Giulia, Nina Schroeder, Linghong Huang, David Boocock, Alessandra Scarpellini, Clare Coveney, Elisa Tonoli, et al. "Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction." Journal of the American Society of Nephrology 29, no. 3 (January 30, 2018): 880–905. http://dx.doi.org/10.1681/asn.2017050479.
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Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF-β1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo, EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD.
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Viteri, Santiago, Werner Hilgers, Fabrice Denis, Elisabeth Quoix, Gilles Robinet, Enriqueta Felip, Rafal Dziadziuszko, et al. "366 Combined exploratory immunophenotyping and transcriptomic tumor analysis in patients treated with OSE2101 vaccine in HLA-A2+ advanced non-small cell lung cancer (NSCLC) from the ATALANTE-1 trial." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A394. http://dx.doi.org/10.1136/jitc-2021-sitc2021.366.
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BackgroundOSE2101 (Tedopi®) is an anticancer vaccine with HLA-A2+ restricted modified epitopes targeting five tumor-associated antigens (TAAs) frequently expressed in lung cancer (CEA, HER2, MAGE2, MAGE3, P53). Step-1 results of the phase III, randomized, open-label ATALANTE-1 study comparing Tedopi® vs standard treatment (SoC) showed a favorable benefit/risk of Tedopi® over SoC (HR 0.71 for overall survival OS) in HLA-A2+ NSCLC patients in 2nd or 3rd line treatment after progression on immune checkpoint blockers (ICB).1 We analyze available tumor biopsies at initial diagnosis from some patients treated with Tedopi® to determine the expression of the 5 TAAs and to identify other tumor factors associated with long-term survival.MethodsTumor biopsies were available for 8 HLA-A2+ (blood test) stage IV NSCLC patients included in the trial. Primary (<12 weeks) and secondary (≥ 12 weeks) resistance to ICB were observed in 3 (38%) and 5 (62%) of patients. Best response to Tedopi® and OS were: 1 partial response (PR) (OS of 33 months), 3 stable disease (SD) (OS of 22, 26 and 41 mo.) and 4 disease progression (PD) (OS of 3, 4, 30 and 31 mo.). HLA-class I, PD-L1, CD8 T-cells, HER2, CEA and P53 tumor expression were evaluated by immunohistochemistry (IHC). NanoString gene expression profiling was performed using the Pan Cancer Immune gene set.ResultsHLA-class I was expressed in all tumor samples. IHC analysis revealed that P53, CEA and HER2 were expressed in 6/7, 5/7 and 0/7 patients, respectively. P53, CEA, HER2, MAGE2, and MAGE3 were detected at RNA level in 5/5 tested patients (table 1). IMMUNOSCORE® IC CD8/PDL1 analysis showed High/High, High/Low and Low/Low scores for 1/7, 1/7 and 5/7 patients, respectively. The High/High IMMUNOSCORE® with a pronounced CD8+ T-cell tumor infiltration was observed in the patient with PR. High percentage of tumor cells expressing P53 (69%–97%) and overexpression of genes associated with activated macrophages (TREM2, MARCO, SLC11A1, CHIT1, SERPINB2) were observed in the PR and SD patients. High IFN-gamma and Expanded Immune Gene Signature scores were observed in long-term survivor patients with secondary resistance to ICB, even after progressive disease.Abstract 366 Table 1Summary of clinical and translational dataCEACarcinoembryonic antigen; HER2: Human Epidermal Growth Factor Receptor-2; ICB: Immune checkpoint blocker; IHC: Immunohistochemistry; ND: Not determined; OS: Overall Survival; Patient ID: Patient identification; PDL1: Programmed death-ligand 1; PFS: Progression-free survival; ssGSEA: Single-sample Gene Set Enrichment Analysis. Blue bars = Length of overall survival; Green bars = Gene Signature upregulation; Red bars = Gene Signature downregulationConclusionsThis study shows that all HLA-A2+ patients (blood test), expressed HLA class I in the tumors at initial diagnosis. Transcriptomic data in the patients that benefited from Tedopi® showed activated macrophage pathway, high IFN-gamma and Expanded Immune Gene Signatures scores. These data will be validated on larger number of patients treated with Tedopi® after the step 2 analysis.AcknowledgementsWe thank Julie Le Boulicaut, François Montestruc and Constant Josse (eXYSTAT, Malakoff, France) for the statistical analysis, and HalioDx for the IHC and NanoString analysis.Trial RegistrationEudraCT number2015-003183-36; NCT number: NCT02654587ReferenceGiaccone, et al. Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (ICI): step 1 results of phase III ATALANTE-1 randomised trial. ESMO meeting 2020, abstract #1260MO.Ethics ApprovalThe study protocol and its related documents (including the patient information and informed consent form) received approval from the Institutional Review Board (IRB), and the Competent Authority prior to study initiation.ConsentEach patient gave his/her written informed consent prior to study enrolment.
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Gacita, Anthony M., Dominic E. Fullenkamp, Joyce Ohiri, Tess Pottinger, Megan J. Puckelwartz, Marcelo A. Nobrega, and Elizabeth M. McNally. "Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression." Circulation 143, no. 13 (March 30, 2021): 1302–16. http://dx.doi.org/10.1161/circulationaha.120.050432.
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Background: Inherited cardiomyopathy associates with a range of phenotypes, mediated by genetic and nongenetic factors. Noninherited cardiomyopathy also displays varying progression and outcomes. Expression of cardiomyopathy genes is under the regulatory control of promoters and enhancers, and human genetic variation in promoters and enhancers may contribute to this variability. Methods: We superimposed epigenomic profiling from hearts and cardiomyocytes, including promoter-capture chromatin conformation information, to identify enhancers for 2 cardiomyopathy genes, MYH7 and LMNA . Enhancer function was validated in human cardiomyocytes derived from induced pluripotent stem cells. We also conducted a genome-wide search to ascertain genomic variation in enhancers positioned to alter cardiac expression and correlated one of these variants to cardiomyopathy progression using biobank data. Results: Multiple enhancers were identified and validated for LMNA and MYH7 , including a key enhancer that regulates the switch from MYH6 expression to MYH7 expression. Deletion of this enhancer resulted in a dose-dependent increase in MYH6 and faster contractile rate in engineered heart tissues. We searched for genomic variation in enhancer sequences across the genome, with a focus on nucleotide changes that create or interrupt transcription factor binding sites. The sequence variant, rs875908, disrupts a T-Box Transcription Factor 5 binding motif and maps to an enhancer region 2 kilobases from the transcriptional start site of MYH7. Gene editing to remove the enhancer that harbors this variant markedly reduced MYH7 expression in human cardiomyocytes. Using biobank-derived data, rs875908 associated with longitudinal echocardiographic features of cardiomyopathy. Conclusions: Enhancers regulate cardiomyopathy gene expression, and genomic variation within these enhancer regions associates with cardiomyopathic progression over time. This integrated approach identified noncoding modifiers of cardiomyopathy and is applicable to other cardiac genes.
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Kim, Hyun Kyu, Su Young Son, Jae Sang Oh, Ye Na Song, Ja Min Byun, Youngil Koh, Junshik Hong, et al. "Metabolic Profiling during Acute Myeloid Leukemia Progression Using Paired Clinical Bone Marrow Serum Samples." Metabolites 11, no. 9 (August 31, 2021): 586. http://dx.doi.org/10.3390/metabo11090586.
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Cellular metabolic changes reflect the characteristics of patients with acute myeloid leukemia (AML) caused by genetic variations, which are important in establishing AML treatment. However, little is known about the metabolic profile of patients with genetic variation-induced AML. Furthermore, the metabolites differ with disease progression. Here, metabolites in the bone marrow serum of ten patients with AML and healthy individuals were analyzed using gas chromatography–mass spectrometry. Compared with that in healthy individuals, expression of most metabolites decreased in patients with AML; hydroxylamine, 2-hydroxybutyric acid, monomethylphosphate, and ethylphosphate expression was unusually increased in the patients. We further examined serial metabolite changes across the initial diagnosis, postremission, and relapse phases. Patients with relapse showed increased metabolite expression compared with those in the diagnostic phase, confirming that patients with AML had aggressively modified leukemic cells. However, a clear difference in metabolite distribution was not observed between the diagnosis and complete remission phases, suggesting that the metabolic microenvironment did not change significantly despite complete remission. Interestingly, metabolite profiles differed with genetic variations in leukemic cells. Our results, which were obtained using paired samples collected during AML progression, provide valuable insights for identifying vulnerable targets in the AML metabolome and developing new treatment strategies.
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Munshi, Nikhil C., Cheng Li, Stephane Minvielle, Samir B. Amin, Philippe Moreau, Florence Magrangeas, Kenneth C. Anderson, and Herve Avet-Loiseau. "Expression Profile Signature to Predict Response to Bortezomib and Dexamethasone Combination Therapy in Newly-Diagnosed Myeloma: Moving towards Prospective Prediction." Blood 112, no. 11 (November 16, 2008): 2746. http://dx.doi.org/10.1182/blood.v112.11.2746.2746.
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Abstract Current therapy for multiple myeloma (MM) remains empiric. Only 30–40% of patients respond to any one agent. Moreover, with each new therapy attempted, patients often experience numerous complications and toxicities requiring specialized intervention. In last 4 years four new agents have been approved for use in MM making selection of effective agents more difficult as well as economically taxing. With the improved understanding of oncogenomics in MM and with an ultimate goal of selecting therapies based on their best chance of success, we have used expression profile of myeloma cells to identify expression signature associated with response or resistance to therapeutic agents. We evaluated 34 newly-diagnosed patients with MM enrolled on IFM protocol 2005-01 and treated with bortezomib and dexamethasone as an induction regimen. 18 patients had achieved CR/nCR while 16 patients had no response or progressive disease on therapy. MM cells were purified from bone marrow samples collected prior to initiation of therapy and expression profile was obtained using Affymetrix Human Exon 1.0 ST arrays and analyzed using the dChip software. We next used the “Sample Classification” module in the dChip software to explore predicting patient response using expression data. When we Use two-sample comparison or ANOVA methods to compare the response and to obtain a gene list, and then use a Linear Discriminant Analysis (LDA) to use these genes as features to train a classifier and predict samples, a prediction accuracy of 97% (33/34) was obtained. For unbiased prediction, we modified dChip to perform a leave-one-out cross-validation. Specifically, for each round, one of the 34 samples is left out and the remaining 33 samples are used to select genes and train the classifier. Then the classifier is used to predict the response of the left-out sample and compare it to the real response of this sample. With this analysis we observed 80% positive predictive value which compares favorably with the present CR ratio in the cohort from which these 34 samples come from. In addition, we also used the same cross-validation method to classify the 8 nCR (immunofixation (IFE) positive CR) versus the 10 CR (IFE negative CR) samples. Although the best achievable overall accuracy is 83%, the accuracy is much more variable than the CR versus NR classification when we vary the gene selection stringency. We also realize and in fact foresee that the expression profile will not be able to predict all patients and due to various factors some samples will not provide clear signature of resistance or sensitivity. A two-group comparison of the response Yes and No samples identified response-related genes. The genes down-regulated in the response group are significantly enriched by genes in Gene Ontology categories “biopolymer glycosylation”, “integral to Golgi membrane”, “transferase activity and gene on chromosome 11q.13. The genes up-regulated in the response group are significantly enriched by genes in Gene Ontology categories “cytoskeleton” and genes on chromosome 12p11 and 4p14. These genes provide a basis for investigating how gene expression and pathways change could affect response to the combination treatment with the two drugs. In conclusion, our preliminary pharmacogenomic studies have confirmed our ability to perform large-scale micro-array profiling from patient bone marrow samples and we have identified gene expression signature associated with responsiveness (CR) versus resistance (NR) to combination of Velcade and dexamethasone. The task ahead is to now prospectively validate our ability to predict whether the combination of bortezomib and dexamethasone will be effective in a given patient.
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Avena, Paola, Arianna De Luca, Adele Chimento, Marta Claudia Nocito, Sara Sculco, Davide La Padula, Lucia Zavaglia, et al. "Estrogen Related Receptor Alpha (ERRα) a Bridge between Metabolism and Adrenocortical Cancer Progression." Cancers 14, no. 16 (August 11, 2022): 3885. http://dx.doi.org/10.3390/cancers14163885.
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The aim of this study was to investigate the metabolic changes that occur in adrenocortical cancer (ACC) cells in response to the modulation of Estrogen Related Receptor (ERR)α expression and the impact on ACC progression. Proteomics analysis and metabolic profiling highlighted an important role for ERRα in the regulation of ACC metabolism. Stable ERRα overexpression in H295R cells promoted a better mitochondrial fitness and prompted toward a more aggressive phenotype characterized by higher Vimentin expression, enhanced cell migration and spheroids formation. By contrast, a decrease in ERRα protein levels, by molecular (short hairpin RNA) and pharmacological (inverse agonist XCT790) approaches modified the energetic status toward a low energy profile and reduced Vimentin expression and ability to form spheroids. XCT790 produced similar effects on two additional ACC cell lines, SW13 and mitotane-resistant MUC-1 cells. Our findings show that ERRα is able to modulate the metabolic profile of ACC cells, and its inhibition can strongly prevent the growth of mitotane-resistant ACC cells and the progression of ACC cell models to a highly migratory phenotype. Consequently, ERRα can be considered an important target for the design of new therapeutic strategies to fight ACC progression.
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Torres-Collado, Antoni X., Ramin Nazarian, and Ali R. Jazirehi. "Rescue of cell cycle progression in BRAFV600E inhibitor–resistant human melanoma by a chromatin modifier." Tumor Biology 39, no. 9 (September 2017): 101042831772162. http://dx.doi.org/10.1177/1010428317721620.
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The BRAFV600E-specific inhibitor vemurafenib blocks mitogen-activated protein kinase pathway and induces cell cycle arrest at G0/G1 phase leading to apoptosis of melanomas. To gain an understanding of the dynamics of cell cycle regulation during vemurafenib therapy, we analyzed several vemurafenib-resistant human melanoma sublines derived from BRAFV600E harboring vemurafenib-sensitive parental lines. Vemurafenib provoked G0/G1 phase arrest in parental but not in vemurafenib-resistant sublines. We hypothesized that refractoriness of vemurafenib-resistant sublines to vemurafenib-mediated cell cycle inhibition can be partially rescued by the chromatin modifier suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid promoted G2/M arrest at expense of S phase irrespective of vemurafenib sensitivity. In parental lines, combination of suberoylanilide hydroxamic acid and vemurafenib induced both G0/G1 arrest and apoptosis, whereas in vemurafenib-resistant sublines combination induced G0/G1 as well as G2/M arrest resulting in dramatic cytostasis. Vemurafenib-resistant sublines exhibited extracellular signal–regulated protein kinases 1 and 2 but not AKT and hyperphosphorylation. Gene expression profiling revealed mitogen-activated protein kinase hyperactivation and deregulations of cyclins and cyclin-dependent kinases in vemurafenib-resistant sublines, all of which were reversed by suberoylanilide hydroxamic acid; changes that may explain the cytostatic effects of suberoylanilide hydroxamic acid. These results suggest that unresponsiveness of vemurafenib-resistant sublines to the biological effects of vemurafenib may be amenable by suberoylanilide hydroxamic acid. These in vitro results, while require further investigation, may provide rational biological basis for combination therapy in the management of vemurafenib-resistant melanoma.
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Reiss, David J., Trevor Do, David Kuo, Vanessa E. Gray, N. Eric Olson, Chung-Wein Lee, Mary H. Young, et al. "Multiplexed Immunofluorescence (IF) Analysis and Gene Expression Profiling of Biopsies from Patients with Relapsed/Refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL) Treated with Lisocabtagene Maraleucel (liso-cel) in Transcend NHL 001 Reveal Patterns of Immune Infiltration Associated with Durable Response." Blood 134, Supplement_1 (November 13, 2019): 202. http://dx.doi.org/10.1182/blood-2019-127683.
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Background: The availability of chimeric antigen receptor (CAR)-modified T cells (CAR T) has profoundly increased therapeutic options for patients (pts) with B cell malignancies, including DLBCL. Liso-cel is an investigational, anti-CD19, defined composition, 4-1BB, CAR T cell product administered at a target dose of CD4+ and CD8+ CAR T cells. To understand tumor microenvironmental (TME) factors affecting short-term and durable responses in pts with R/R DLBCL who received liso-cel in the TRANSCEND NHL 001 study, we conducted multiplexed IF analyses of 111 DLBCL biopsies for 83 pts obtained at baseline (n=58) and approximately 11 days (D11) (n=53; 28 paired) after liso-cel infusion (NCT02631044). Methods: We employed three 5-plex IF panels, consisting of antibodies detecting (1) B cell (CD19, CD20) and T cell lineage (CD4, CD8, EGFR) markers, (2) immunosuppressive markers (CD163, FoxP3, CD73, IDO1, PD-L1), and (3) functional markers (CD3, Ki67, GZMB, PD-1, EGFR). Liso-cel expresses a truncated EGFR (EGFRt), and fluorescent anti-EGFR was used to identify CAR T cells within the tumor biopsies. We also performed bulk tumor RNA profiling for an overlapping subset of 50 baseline biopsies and 37 D11 biopsies (11 paired). We investigated the association of differences in marker densities for pts with best overall response (BOR) of complete response (CR), and progressive disease (PD). Baseline and D11 biopsy findings were correlated with early responses at ~1 month (M1) posttreatment (PD n=16; CR n=42) and durable responses at ~9 months (M9) posttreatment (PD n=76; CR n=32; 55 pts evaluated at both M1 and M9). We investigated how baseline and D11 densities, with spatial distinction between tumoral and peritumoral regions, correlated with early and durable responses. All comparisons describe differences in median densities, and have statistical significance reported with uncorrected P values assessed via the (unpaired) Wilcoxon-Mann-Whitney nonparametric test. Results: Signals in baseline biopsies that correlated with early (M1) response differed from those that correlated with durable (M9) CR. A 21% higher baseline presence of PD-1+ T cells was associated with pts who achieved early CR at M1 vs pts who had PD at M1 (P=0.007). Pts with durable CR at M9 had 39% lower baseline levels of CD163+ macrophages (P=0.019) and 270% higher levels of CD73+ cells (P=0.028) than those with PD at M9. On-treatment (D11) tumors of pts with both early and durable CR had 28% higher levels of EGFRt+ (CAR T) CD8+ T cells (P=0.022), and 810% higher EGFRt- (non-CAR T) CD4+ (but notably, not CD8+; P=0.28) T cells (P=0.009). We also investigated changes in marker densities between baseline and on-treatment (D11) biopsies, and found that pts with durable CR at M9 had decreased on-treatment B cell densities (P=0.029), and increased densities of CD8+ GZMB+, Ki67+, and/or PD-1+ CAR (P=0.001) as well as non-CAR T (P=0.017) cells. Pts with durable CR also had a 29% increase in tumor-associated CD163+ macrophages at D11 relative to baseline (P=0.033). While the accessibility of spatial arrangements and multilabeled cells from IF enables a more nuanced picture of the TME, many of the general trends described above are concordant with those observed in bulk tumor RNA sequencing. Lower baseline expression of CD163 (P=0.021) and higher expression of CD73 (P=0.054) were seen in pts with durable CR. Additionally, elevated on-treatment (D11) expression of CD3E, CD4, and liso-cel (P<0.001) supports the IF finding of greater endogenous and CAR T cell infiltration in pts who responded to treatment. Moreover, pts with a CR at M9 had increased CD163 expression measured at D11 relative to baseline (P<0.001). Conclusions: Overall, these data suggest that increased infiltration of tumor-specific CAR T cells upon initial treatment with liso-cel helped establish an active immune response, and that recruitment of additional functional endogenous (particularly CD4+) T cells correlated with durable response. Higher numbers of activated/functional T cells and lower numbers of macrophages prior to treatment also correlated with durable response to liso-cel. Thus, tumors in responders may already have had a baseline TME in which T cells could infiltrate and respond to antigen. This may have promoted the success of CAR T cell entry into tumors and the subsequent recruitment and activation of endogenous lymphocytes that support their function. Disclosures Reiss: Celgene Corporation: Employment, Equity Ownership. Do:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Kuo:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Gray:Celgene Corporation: Employment, Equity Ownership. Olson:Celgene Corporation: Employment, Equity Ownership. Lee:Celgene Corporation: Employment, Equity Ownership. Young:Celgene Corporation: Employment, Equity Ownership. Srinivasan:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Gray:Celgene: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Couto:Celgene Corporation: Employment, Equity Ownership. Dubovsky:Celgene: Employment. Schmitz:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership.
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Germanguz, Igal, Jenny C. Park, Jessica Cinkornpumin, Aryeh Solomon, Minori Ohashi, and William E. Lowry. "TDG regulates cell cycle progression in human neural progenitors." F1000Research 7 (April 26, 2018): 497. http://dx.doi.org/10.12688/f1000research.13801.1.
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Background: As cells divide, they must both replicate their DNA and generate a new set of histone proteins. The newly synthesized daughter strands and histones are unmodified, and must therefore be covalently modified to allow for transmission of important epigenetic marks to daughter cells. Human pluripotent stem cells (hPSCs) display a unique cell cycle profile, and control of the cell cycle is known to be critical for their proper differentiation and survival. A major unresolved question is how hPSCs regulate their DNA methylation status through the cell cycle, namely how passive and active demethylation work to maintain a stable genome. Thymine-DNA glycosylase (TDG), an embryonic essential gene, has been recently implicated as a major enzyme involved in demethylation. Methods: We use human pluripotent stem cells and their derivatives to investigate the role of TDG in differentiation and proliferation. To perform loss of function of TDG, RNA Interference was used. To study the cell cyle, we engineered human pluripotent stem cells to express the FUCCI tool which marks cells at various stages of the cell cycle with distinct patterns of fluorescent proteins. We also used cell cycle profiling by FACS, and DNA methylation analysis to probe a connection between DNA demethylation and cell cycle. Results: Here we present data showing that TDG regulates cell cycle dynamics in human neural progenitors (NPCs) derived from hPSCs, leading to changes in cell cycle related gene expression and neural differentiation capacity. These data show that loss of TDG function can block differentiation by driving proliferation of neural progenitors. We also identify specific cell cycle related genes whose expression changes upon loss of TDG expression. Conclusions: These observations suggest that TDG and active demethylation play an important role in hPSC cell cycle regulation and differentiation.
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Kelly, Lori A., Ali H. Zaidi, Mark Barlek, Rachael Kreft, Ashten Omstead, Juliann Kosovec, Yoshihiro Komatsu, and Blair A. Jobe. "Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 28. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.28.
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28 Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.
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Gaipov, Abduzhappar, Zhalaliddin Makhammajanov, Zhanna Dauyey, Zhannur Markhametova, Kamilla Mussina, Assem Nogaibayeva, Larissa Kozina, et al. "Urinary Protein Profiling for Potential Biomarkers of Chronic Kidney Disease: A Pilot Study." Diagnostics 12, no. 11 (October 25, 2022): 2583. http://dx.doi.org/10.3390/diagnostics12112583.
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Proteinuria is a risk factor for chronic kidney disease (CKD) progression and associated complications. However, there is insufficient information on individual protein components in urine and the severity of CKD. We aimed to investigate urinary proteomics and its association with proteinuria and kidney function in early-stage CKD and in healthy individuals. A 24 h urine sample of 42 individuals (21-CKD and 21-healthy individuals) was used for mass spectrometry-based proteomics analysis. An exponentially modified protein abundance index (emPAI) was calculated for each protein. Data were analyzed by Mascot software using the SwissProt database and bioinformatics tools. Overall, 298 unique proteins were identified in the cohort; of them, 250 proteins belong to the control group with median (IQR) emPAI 39.1 (19–53) and 142 proteins belong to the CKD group with median (IQR) emPAI 67.8 (49–117). The level of 24 h proteinuria positively correlated with emPAI (r = 0.390, p = 0.011). The emPAI of some urinary proteomics had close positive (ALBU, ZA2G, IGKC) and negative (OSTP, CD59, UROM, KNG1, RNAS1, CD44, AMBP) correlations (r < 0.419, p < 0.001) with 24 h proteinuria levels. Additionally, a few proteins (VTDB, AACT, A1AG2, VTNC, and CD44) significantly correlated with kidney function. In this proteomics study, several urinary proteins correlated with proteinuria and kidney function. Pathway analysis identified subpathways potentially related to early proteinuric CKD, allowing the design of prospective studies that explore their response to therapy and their relationship to long-term outcomes.
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Vieira, Filipa Quintela, Pedro Costa-Pinheiro, João Ramalho-Carvalho, Andreia Pereira, Francisco Duarte Menezes, Luís Antunes, Isa Carneiro, Jorge Oliveira, Rui Henrique, and Carmen Jerónimo. "Deregulated expression of selected histone methylases and demethylases in prostate carcinoma." Endocrine-Related Cancer 21, no. 1 (November 7, 2013): 51–61. http://dx.doi.org/10.1530/erc-13-0375.
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Prostate cancer (PCa), a leading cause of cancer-related morbidity and mortality, arises through the acquisition of genetic and epigenetic alterations. Deregulation of histone methyltransferases (HMTs) or demethylases (HDMs) has been associated with PCa development and progression. However, the precise influence of altered HMTs or HDMs expression and respective histone marks in PCa onset and progression remains largely unknown. To clarify the role of HMTs and HDMs in prostate carcinogenesis, expression levels of 37 HMTs and 20 HDMs were assessed in normal prostate and PCa tissue samples by RT-qPCR.SMYD3,SUV39H2,PRMT6,KDM5A, andKDM6Awere upregulated, whereasKMT2A-E (MLL1-5)andKDM4Bwere downregulated in PCa, compared with normal prostate tissues. Remarkably,PRMT6was the histone modifier that best discriminated normal from tumorous tissue samples. Interestingly,EZH2andSMYD3expression levels significantly correlated with less differentiated and more aggressive tumors. Remarkably,SMYD3expression levels were of independent prognostic value for the prediction of disease-specific survival of PCa patients with clinically localized disease submitted to radical prostatectomy. We concluded that expression profiling of HMTs and HDMs, especiallySMYD3, might be of clinical usefulness for the assessment of PCa patients and assist in pre-therapeutic decision-making.
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Lisberg, Aaron Elliott, Bin Liu, Ramin Salehi-Rad, Jay M. Lee, Linh Tran, Kostyantyn Krysan, Raymond Lim, et al. "Phase I trial of in situ vaccination with autologous CCL21-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced NSCLC." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS9135. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps9135.
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TPS9135 Background: Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those that are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment promoting both local and systemic T cell activation. The chemokine CCL21 promotes co-localization of naive T cells and antigen-experienced dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust CCL21-DC mediated antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC that are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, or 3x107) when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment. Clinical trial information: NCT03546361.
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Sweeney, Jenna Geddes, Jennifer Liang, Nicholas Giovannone, Lana Schaffer, Steven R. Head, Aristotelis Antonopoulos, Stuart M. Haslam, Hans R. Widlund, and Charles J. Dimitroff. "“I”-branched Carbohydrates Negatively Regulate Galectin-3-binding and Melanoma Malignancy." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 144.17. http://dx.doi.org/10.4049/jimmunol.196.supp.144.17.
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Abstract Malignant transformation is often associated with aberrant glycosylation of cell surface proteins. Commonly observed changes in glycan structures include increased presence of sialic acid, altered expression of mucins, and abnormal branching of N-glycans. Increasing evidence supports the idea that the presence of certain glycans correlate with cancer progression by affecting tumor cell invasiveness, ability to bind pro-tumorigenic galectins, and by promoting metastasis to distant organs. Taking this relationship into consideration, we conducted MALDI-TOF mass spectrometry on cell surface glycans as well as glycomic gene profiling from normal human epidermal melanocytes (NHEM) and human metastatic melanoma (MM) cells. We found that a defining feature between NHEMs and MMs was the relative level of “I”-branched and “i”-linear poly-N-acetyllactosamines on N-glycans. While NHEM predominantly expressed “I”-branched structures, MMs expressed “i”-linear modified N-glycans. Furthermore, glycomic gene profiling and confirmatory RT-qPCR data showed that the “I”-branching β1,6 N-acetylglucosaminyltransferase 2, GCNT2, is decreased in MM compared with NHEMs. With regards to its role in malignancy, we found that GCNT2 functioned as a negative regulator of galectin-3 (Gal-3) binding. GCNT2 overexpression in human MM cells inhibited Gal-3 mediated ERK1/2 phosphorylation and significantly reduced primary tumor growth. While GCNT2 knockdown in human MM cells promoted Gal-3 mediated ERK1/2 phosphorylation and significantly enhanced primary tumor growth. These findings highlight new glycobiological insights into melanoma development, implicating GCNT2 as a negative regulator of Gal-3 binding and melanoma malignancy.
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Tabolacci, Claudio, Martina Cordella, Sabrina Mariotti, Stefania Rossi, Cinzia Senatore, Carla Lintas, Lauretta Levati, et al. "Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals." Biomedicines 9, no. 1 (January 15, 2021): 79. http://dx.doi.org/10.3390/biomedicines9010079.
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The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.
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Pilon, Andre M., Murat O. Arcasoy, Holly K. Dressman, Serena E. Vayda, Yelena D. Maksimova, Jose I. Sangerman, Patrick G. Gallagher, and David M. Bodine. "Failure of Terminal Erythroid Differentiation in EKLF-Deficient Mice Is Associated with Cell Cycle Perturbation and Reduced Expression of E2F2." Molecular and Cellular Biology 28, no. 24 (October 13, 2008): 7394–401. http://dx.doi.org/10.1128/mcb.01087-08.
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ABSTRACT Erythroid Krüppel-like factor (EKLF) is a Krüppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf −/− ) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differentiation in Eklf −/− embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild-type and Eklf −/− early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf −/− early erythroid progenitor cells, which showed a delay in the G1-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.
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Xie, Wensheng, Robert S. Ames, and Hu Li. "A Cell-Based High-Throughput Screening Assay to Measure Cellular Histone H3 Lys27 Trimethylation with a Modified Dissociation-Enhanced Lanthanide Fluorescent Immunoassay." Journal of Biomolecular Screening 17, no. 1 (November 15, 2011): 99–107. http://dx.doi.org/10.1177/1087057111422378.
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Histone proteins are subject to several modifications, including phosphorylation, acetylation, methylation, sumoylation, and ubiquitination. These posttranslational modifications play critical roles in chromatin structure and gene transcription. Because of their involvement in the progression of a variety of diseases, histone modifications are attracting increased attention. We report herein a high-throughput DELFIA assay to quantify H3K27me3 in the prostate cancer cell line, PC3. Using a high binding MaxiSorp plate, we were able to eliminate the need for the capture antibody. We also developed an effective method, a combination of “freeze-thaw” and 0.2 N HCl, to extract histone proteins in PC3 cells cultured in a 384-well plate. To compensate for cell viability change, we normalized H3K27me3 signal to the total amount of H3 in each sample well. As a result, we show that the assay has a good dynamic range with a robust assay window. Using a methlytransferase inhibitor, DZNep, we show that the change of H3K27me3 signal is target specific. This method simplifies the logistics in screening and profiling and reduces the cost per well to an acceptable level for high-throughput screening. The findings presented here should be applicable to other assays involving binding and extraction of histone proteins.
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Zhang, Wei, Jinke Sui, Xianrui Wu, Fuao Cao, Guanyu Yu, Chenyang Wang, Zhihong Zhang, et al. "DNA methylation profiling from circulating tumor DNA for early-detection of colorectal cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15076-e15076. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15076.
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e15076 Background: Colorectal cancer (CRC) develops as a result of neoplastic progression, which often takes decades, providing a window for early detection. Unfortunately, there has been little success in developing blood-based screening method due to the low amount of ctDNA present in the circulation, especially in patients with early stage disease. The role of aberrant DNA methylation, occurring very early in tumorigenesis, has been well elucidated. In this prospective study, we evaluated the potentiality of DNA methylation status obtained from ctDNA as an early detection method. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were extracted using modified wald-test with an adjusted p-value < 0.05 and fold-change > 2. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. We performed targeted bisulfite sequencing on plasma samples of 67 (stage I: 13, II:29, III: 23, IV: 2) Chinese CRC patients and 144 healthy individuals to construct a model for deriving markers that are differentially methylated and their associated weight. The model was validated in 2 independent cohorts. Results: We constructed a model using a support vector machine (SVM)-based machine learning classifier based on top 4,000 differentially methylated regions (DMRs) selected by random forest between tumor and normal plasma samples. Subsequently, 5-fold cross-validation with 100-time repeats were performed to gain a robust estimation of model performance, achieving a sensitivity of 91%, specificity of 98% and area under curve (AUC) of 98.6%. The model was subsequently validated in 2 independent cohorts: one consisted of 57 stage I-III CRC patients and 74 healthy individuals and another one with 47 stage IV patients and the same 74 healthy individuals. The model yielded a sensitivity of 83% and 95% for the early and late stage cohorts, respectively. A specificity of 95% was obtained for both cohorts. Conclusions: Our findings demonstrated the potential of profiling DNA methylation, which can effectively distinguish cancerous from healthy, for the purpose of screening. This method has potential to serve as a supplementary or alternative approach in early detection.
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Lee, Choong-kun, Jaekyung Cheon, Hong Jae Chon, Min Hwan Kim, Jin Won Kim, Myung Ah Lee, Hyung Soon Park, Myoung Joo Kang, Joung-Soon Jang, and Hye Jin Choi. "A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS4161. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4161.
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TPS4161 Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.
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Cattrini, Carlo, Marcello Manfredi, Paola Barboro, Marco Ghirimoldi, Alessia Mennitto, Veronica Martini, Federica Biello, et al. "Lipidomic profiling in patients with heavily pretreated castration-resistant prostate cancer." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 174. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.174.
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174 Background: Despite the advent of chemotherapy and androgen-receptor signaling inhibitors (ARSi), patients with metastatic castration-resistant prostate cancer (mCRPC) still show poor prognosis and reduced survival. The selective pressure induced by treatments favors the activation of alternative metabolic pathways that allow the persistence of cancer cells in unfavorable conditions. This study aimed at assessing the lipidomic profiles of patients with mCRPC, in order to identify lipid species potentially useful to predict for prognosis and response to therapies. Methods: Plasma samples were collected from patients with mCRPC who were starting a first-line treatment for mCRPC (1L) (n = 30) and from those who had already received at least two lines of treatment for mCRPC ( > 2L) (n = 19), including at least one ARSi and a taxane. Lipids were extracted from plasma samples using a modified Matyash method employing a mix of cold MeOH and MTBE and containing a mix of deuterated standards (Splash Lipidomix). Lipids were then analyzed with an untargeted lipidomic approach using an UHPLC Vanquish system coupled with a Q-Exactive Plus instrument. T-test was then applied to identify lipid species and classes that were differentially expressed in 1L vs < 2L patients. Results: We identified and quantified a total of 907 plasma lipids. Overall, 68 lipid species were significantly dysregulated in > 2L compared to 1L plasma samples. 56 species were found to be upregulated, whereas 12 were downregulated, with a fold change (FC) > 1.3 or < 0.75 and a p-value < 0.05. At the level of lipid classes, > 2L patients showed higher levels of acylcarnitine (CAR), diacylglycerols (DG), phosphatidylethanolamine (PE) and triacylglycerols (TG). The following lipids showed the highest FC: DG28:2 = 4.2; CAR14:0 = 3.7; CAR20:1 = 2.6; CAR18:0 = 2.3; PE40:6 = 2.3. Conversely, significantly lower levels of specific phosphatidylcholines (PC) and sterols (ST) were found in > 2L compared to 1L patients. The following species showed the lowest FC: PCO-39:3 = 0.52; ST29:1;O;S = 0.55; PC36:5 = 0.55; PC36.4 = 0.60. These results suggest that patients with strongly pretreated mCRPC show higher levels of lipid species involved in the switch between the glucose and fatty acid metabolism. We also found a dysregulation of ceramides and sphingomyelins which are well-known lipid species involved in apoptosis and cancer progression. Specific lipids warrant further investigation to be used as potential prognostic and predictive biomarkers in patients with mCRPC. Conclusions: Using a quantitative mass spectrometry approach, we investigated the dysregulation of lipids and lipid metabolism in mCRPC patients at different disease stages. We found that specific lipid species show differential levels in patients pretreated with ARSi and chemotherapy, compared to those who are naïve to these treatments, paving the way for further investigations in this field.
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Czuczman, Myron S., Andrew Davies, Kim M. Linton, Nina Wagner-Johnston, Randy D. Gascoyne, David A. Eberhard, Gilles Salles, et al. "A Phase 2/3 Multicenter, Randomized Study Comparing the Efficacy and Safety of Lenalidomide Versus Investigator’s Choice in Relapsed/Refractory DLBCL." Blood 124, no. 21 (December 6, 2014): 628. http://dx.doi.org/10.1182/blood.v124.21.628.628.
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Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) comprising 3 molecular subtypes: germinal center B-cell (GCB), activated B-cell (ABC) and class III. ABC patients (pts) have a poor prognosis. The immunomodulatory drug lenalidomide (Len) produces durable responses in pts with aggressive NHL (Witzig 2011), with preferential activity reported in non-GCB DLBCL (Hernandez-Ilizaliturri 2011). Methods: This randomized, multicenter, open-label, phase 2/3 study was conducted to determine the efficacy and safety of single-agent Len vs single-agent investigator’s choice (IC) in relapsed/refractory DLBCL pts who received ≥2 prior therapies, or were ineligible for stem cell transplantation or further combination chemotherapy. DLBCL subtype (GCB vs non-GCB) was determined by a central pathology lab using immunohistochemistry (IHC) per the Hans method (Hans 2004). Pts were stratified by subtype, then randomized 1:1 to receive Len (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin) until progressive disease (PD), unacceptable toxicity, or voluntary withdrawal. In the event of radiologically confirmed PD, pts in the IC arm were allowed to cross over to Len. The primary endpoint for Stage 1 was overall response rate (ORR), as determined by an Independent Response Assessment Committee. Progression-free survival (PFS), overall survival (OS) and subtype analysis using gene expression profiling (GEP) were exploratory endpoints. Concordance of GEP and IHC was evaluated from 3 separate laboratories. Results: IHC subtyping agreement rate among the 3 laboratories ranged from 87.5%-97.9%, and sensitivity of IHC to detect ABC or GCB subtypes vs GEP ranged from 92.3%-100.0%. By IHC, 102 DLBCL pts (GCB, n=48; non-GCB, n=54) were treated with ≥1 dose of Len or IC (modified intent-to-treat population) in Stage 1. In this heavily pretreated population, >90.0% of pts received ≥2 prior systemic chemotherapies; 25 pts in Len and 32 pts in IC received ≥3 prior systemic chemotherapy regimens. Median age was 65 y in the IC arm vs 69 y in the Len arm. Twenty-nine pts crossed over from IC to Len after confirmed PD. All pts, regardless of subtype or therapy group, experienced ≥1 treatment-emergent adverse event, with neutropenia, anemia, and thrombocytopenia being the most common. Efficacy data are presented in the Table. Pts with GCB or non-GCB DLBCL (per IHC) treated with Len had similar ORR, but the data suggested greater improvements in PFS and OS with Len vs IC in the non-GCB pts. In an exploratory analysis of pts subtyped by GEP, ABC pts treated with Len vs IC-treated showed greater improvements in ORR, PFS, and OS compared with GCB pts. Prespecified criterion to advance to Stage 2 was a 2-sided 15% significance level in ORR in favor of Len based on IHC-defined subtype. The data did not fulfill this requirement, and Stage 2 was not opened. Conclusion: Len monotherapy showed clinical activity in heavily pretreated pts with DLBCL. The data suggest improved ORR, PFS, and OS with Len vs IC in the non-GCB population as defined by IHC, and the difference appears to be more pronounced in the ABC population as defined by GEP. Subtyping by GEP is warranted in further studies of Len in DLBCL. Abstract 628. Table 1.Table. Efficacy DataBy IHCBy GEPOverallGCBNon-GCBGCBABCLen(n=51)IC(n=51)Len(n=23)IC(n=25)Len(n=28)IC(n=26)Len(n=14)IC(n=16)Len(n=11)IC(n=16)ORR, % (95% CI)27.5 (15.9-41.7)11.8 (4.4-23.9) 26.1 (10.2-48.4)12.0 (2.5-31.2)28.6 (13.2-48.7)11.5 (2.4-30.2)21.4 (4.7-50.8)12.5 (1.6-38.3)45.5 (16.7-76.6)18.8 (4.0-45.6)P Value .079 .279 .179 .642 .206PFS, med wk (95% CI)13.6 (8.6-17.7)7.9 (6.3-9.0) 10.1 (8.3-22.3)29.0 (6.3-20.6)15.1 (8.3-24.1)7.1 (5.3-8.4)13.2 (8.3-24.9)7.1 (6.0-20.6)82.0 (7.3-NA)6.2 (4.3-10.1)P Value .041 .550 .021 .506 .105HR (95% CI) 0.64 (0.41-0.99) 0.82 (0.43-1.57) 0.50 (0.27-0.92) 0.77 (0.35-1.68) 0.44 (0.15-1.23)OS, med wk (95% CI)31.0 (16.6-41.3)24.6 (12.7-33.9) 30.0 (14.9-44.4)24.9 (13.7-58.3)32.3 (15.9-48.1)20.4 (10.3-33.9)30.0 (18.0-34.6)20.1 (13.7-36.9)108.4 (9.6-108.4)18.6 (6.6-48.0)P Value .673 .526 .253 .767 .144HR (95% CI) 0.91 (0.59-1.41) 1.23 (0.65-2.34) 0.70 (0.38-1.30) 1.12 (0.52-2.42) 0.47 (0.17-1.33) Abbreviations: CI, confidence interval; HR, hazard ratio; med, median; NA, not applicable/not available. Disclosures Czuczman: Celgene: Consultancy. Off Label Use: This abstract describes a clinical trial of lenalidomide, which is an orally-available immunomodulatory agent under investigation for treating patients with diffuse large B-cell lymphoma.. Davies:GlaxoSmithKlein: Research Funding; Hoffman La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Gascoyne:Celgene: Consultancy, Research Funding. Salles:Pfizer: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Hoffman La Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Witzig:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Mundipharma: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Millennium Takeda: Honoraria; Celgene: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees. Wright:Celgene: Research Funding. Staudt:Celgene Corporation: Research Funding. Repici:Celgene: Employment. Song:Celgene: Employment. Manzke:Celgene: Employment.
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Graham, Trevor A. "Abstract IA024: The role of the epigenome and phenotypic plasticity in colorectal cancer evolution." Cancer Research 82, no. 10_Supplement (May 15, 2022): IA024. http://dx.doi.org/10.1158/1538-7445.evodyn22-ia024.
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Abstract The evolutionary dynamics of colorectal metastasis and the role of the epigenome in disease progression remain to be fully determined. We have used multi-region, multi-omic profiling (DNA, RNA and chromatin), together with computational modelling, of a prospectively collected cohort of primary CRCs (pCRCs) and DNA and RNA analysis of a retrospective series of metastatic CRCs (mCRCs) to define pCRC biology and track clonal evolution from primary tumour to metastasis. Computational analysis of multi-region sequencing data provided a sensitive test confirming subclonal selection is rare in pCRCs. We detected substantial epigenetic rewiring at the outset of pCRC formation, implicating changes in chromatin accessibility in the initial genesis of CRCs. Using DNA to trace clonal ancestry and overlaying RNA to measure gene expression phenotypes, we observe widespread gene expression changes without underlying clonal selection, indicative that pCRC cells are phenotypically plastic. In mCRCs, we observe that the karyotype of the primary tumour is often not substantially modified in metastasis, across multiple organs, through treatment and over substantial periods of time. This is suggestive that stabilising selection, acting on copy number alterations, constrains karyotype evolution. Paired analysis of DNA and RNA in metastasis indicate that the phenotypic plasticity persists during metastatic spread. Epigenetic rewiring and phenotypic plasticity play potentially causative roles in the genesis and progression of colorectal cancer. Citation Format: Trevor A. Graham. The role of the epigenome and phenotypic plasticity in colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA024.
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Silk, Ann W., Nicole R. LeBoeuf, Guilherme Rabinowits, Igor Puzanov, Melissa Amber Burgess, Sumana Devata, Dirk Moore, et al. "A phase II study of talimogene laherparepvec followed by talimogene laherparepvec + nivolumab in refractory T cell and NK cell lymphomas, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and other rare skin tumors (NCI #10057)." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): TPS219. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.tps219.
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TPS219 Background: Talimogene laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of talimogene laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral talimogene laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed therapy is allowed. If an objective response is not achieved by Week 12, the PD-1 blocking antibody nivolumab will be added. The primary endpoint is the response rate with talimogene laherparepvec and secondary endpoints include response rate with the combination and overall survival. Using a two-stage design, if 1 or more response is observed in the first 9 patients in each parallel cohort, 8 additional patients will be accrued for a total sample size of 36 to 68 patients across the 4 disease cohorts. Tumor biopsies of injected lesions are mandatory at baseline and Week 6, and optional at Week 16 and the time of progression. Optional biopsies of non-injected lesions (when applicable) at Week 6 and 16 will be analyzed to identify biomarkers of systemic immunity. Tumor tissue and/or blood will be assayed for PD-L1 expression, RNA profiling, immune cell profiling, HVEM, NECTIN 1/2, IDO, tryptophan and L-kynurenine, mutational load, TIL TCR clonality, and prior exposure to herpes simplex type 1 virus and Merkel cell polyomavirus. Clinical trial information: NCT02978625.
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Epelbaum, Ron, Einat Shacham-Shmueli, Ravit Geva, and Ayala Hubert. "Molecular profiling (MP)-selected therapy for the treatment of patients with advanced pancreaticobiliary cancer (PBC)." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 195. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.195.
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195 Background: For patients (pts) with advanced PBC who are able to pursue additional therapy, treatment selection is often empiric and clinical benefits are usually modest. Our goal was to study clinical outcomes of MP-guided treatment in advanced PBC. Methods: This retrospective analysis included pts with advanced PBC whose tissue samples underwent MP (IHC, microarray [MA], and sequencing analyses) using Target Now (Caris Life Sciences, Irving, TX). These pts received ≥1 lines of therapy for advanced PBC before their treatment was guided by MP. The MP-guided therapy was considered to have clinical benefit if the TTP ratio between the longest TTP on MP-guided therapy and the TTP on the last therapy pre-MP was ≥1.3. Results: Out of 20 pts included in the analysis, 16 had advanced cancer of the pancreas. Median age was 59 yrs (range: 30-81), 85% were male, and 60% had PS of 1. Pts had 1-4 treatment regimens (median: 1) prior to MP. MP identified 1-7 (median: 4) actionable targets per pt. The most commonly identified targets by IHC were: negative or low TS (80%), high TOPO1 (70%), negative or low ERCC1 (52%), and high SPARC (40%). In all 14 pts that had MA results, multiple actionable targets were identified. Of 14 pts with KRAS sequencing analysis, 10 pts (71%) had mutations. Post-MP, pts had 1-4 (median: 1) treatment regimens, most commonly FOLFIRI/XELIRI, FOLFOX/XELOX, capecitabine, and nab-paclitaxel. The total number of regimens post-MP was 33, of which 29 were evaluable for decision impact analysis. In 24 (83%) of cases, treatment decision was modified due to the MP results. Out of the 20 pts, 4 received ≤1 cycle of MP-guided therapy during rapidly progressing disease and were excluded from the clinical outcome analysis. Of the 16 evaluable pts, 6 (37.5%) had a TTP ratio of ≥1.3 (one-sided exact binomial test vs a null hypothesis of ≤15% with TTP ratio ≥1.3, P=0.0056; therefore the null hypothesis is rejected). Conclusions: In our retrospective analysis of a small, yet well-defined, cohort of pts with advanced PBC, MP often influenced treatment decisions and over a third of pts experienced a longer TTP (compared to the last regimen pre-MP), highlighting the promise in MP for treatment selection.
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Han, P., C. Hou, X. Zheng, L. Cao, X. Shi, X. Zhang, H. Ye, T. Li, F. Hu, and Z. Li. "AB0058 SERUM ANTIGENOME PROFILING REVEALS DIAGNOSTIC MODELS FOR RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1162.2–1163. http://dx.doi.org/10.1136/annrheumdis-2022-eular.613.
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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint damage, systemic inflammation and early mortality. Though the precise molecular mechanism in the triggering immune response are not fully understood, the emergence of antibodies against self-antigens can serve as diagnostic biomarker. Multiple antigens have been confirmed. However, the profiling of serum antigen, antigenome, remains poorly known.ObjectivesThe study aimed to investigate the serum antigenomic profiling and determine potential diagnostic biomarkers using label-free proteomic technology implemented with machine-learning algorithm.MethodsWe captured serum antigens from a cohort consisting of 60 RA patients (45 ACPA-positive RA patients and 15 ACPA-negative RA patients), sex- and age-matched 30 osteoarthritis patients and 30 healthy controls. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed. We then trained a machine learning model to classify RA, ACPA-positive RA and ACPA-negative RA based on proteomic data and validated in the cohort.ResultsWe identified 62, 71 and 49 differentially expressed proteins (DEPs) in RA, ACPA-positive RA and ACPA-negative RA respectively, compared to OA and healthy controls. Among these DEPs, the pathway enrichment analysis and protein-protein interactions networks were conducted. Three panels were constructed to classify RA, ACPA-positive RA and ACPA-negative RA using random forest models algorithm based on the molecular signature of DEPs, whose area under curve (AUC) were calculated as 0.9949 (95% CI = 0.9792-1), 0.9913 (95%CI = 0.9653-1) and 1.0 (95% CI = 1-1).ConclusionThis study presented serum antigen profiling of RA. Among them, three panels of antigens were identified to classify RA, ACPA-positive and ACPA-negative RA patients as diagnostic biomarkers.References[1]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet (London, England). (2016) 388: 2023-38. doi: 10.1016/S0140-6736(16)30173-8[2]De Rycke L, Peene I, Hoffman IE, Kruithof E, Union A, Meheus L, et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis. (2004) 63: 1587-93. doi: 10.1136/ard.2003.017574[3]Kampstra ASB, Dekkers JS, Volkov M, Dorjée AL, Hafkenscheid L, Kempers AC, et al. Different classes of anti-modified protein antibodies are induced on exposure to antigens expressing only one type of modification. Ann Rheum Dis. (2019) 78: 908-16. doi: 10.1136/annrheumdis-2018-214950[4]Liao W, Li Z, Li T, Zhang Q, Zhang H, Wang X. Proteomic analysis of synovial fluid in osteoarthritis using swath‑mass spectrometry. Mol Med Rep. (2018) 17: 2827-36. doi: 10.3892/mmr.2017.8250[5]Peffers MJ, Smagul A, Anderson JR. Proteomic analysis of synovial fluid: current and potential uses to improve clinical outcomes. Expert Rev Proteomic. (2019) 16: 287-302. doi:10.1080/14789450.2019.1578214[6]Swan AL, Mobasheri A, Allaway D, Liddell S, Bacardit J. Application of machine learning to proteomics data: classification and biomarker identification in postgenomics biology. Omics: a journal of integrative biology. (2013) 17: 595-610. doi: 10.1089/omi.2013.0017[7]Mahler M, Martinez-Prat L, Sparks JA, Deane KD. Precision medicine in the care of rheumatoid arthritis: focus on prediction and prevention of future clinically-apparent disease. Autoimmun Rev. (2020) 19: 102506. doi: 10.1016/j.autrev.2020.102506[8]Mun S, Lee J, Park A, Kim HJ, Lee YJ, Son H, et al. Proteomics approach for the discovery of rheumatoid arthritis biomarkers using mass spectrometry. Int J Mol Sci. (2019) 20. doi: 10.3390/ijms20184368[9]Li K, Mo W, Wu L, Wu X, Luo C, Xiao X, et al. Novel autoantibodies identified in acpa-negative rheumatoid arthritis. Ann Rheum Dis. (2021). doi: 10.1136/annrheumdis-2020-218460Figure 1.Study overview and antigenome characterizationDisclosure of InterestsNone declared
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Phillipou, Alexander N., Charles S. Lay, Charlotte E. Carver, Cassie Messenger, John P. Evans, Antonia J. Lewis, Laurie J. Gordon, et al. "Cellular Target Engagement Approaches to Monitor Epigenetic Reader Domain Interactions." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 2 (December 25, 2019): 163–75. http://dx.doi.org/10.1177/2472555219896278.
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Malfunctions in the basic epigenetic mechanisms such as histone modifications, DNA methylation, and chromatin remodeling are implicated in a number of cancers and immunological and neurodegenerative conditions. Within GlaxoSmithKline (GSK) we have utilized a number of variations of the NanoBRET technology for the direct measurement of compound–target engagement within native cellular environments to drive high-throughput, routine structure–activity relationship (SAR) profiling across differing epigenetic targets. NanoBRET is a variation of the bioluminescence resonance energy transfer (BRET) methodology utilizing proteins of interest fused to either NanoLuc, a small, high-emission-intensity luciferase, or HaloTag, a modified dehalogenase enzyme that can be selectively labeled with a fluorophore. The combination of these two technologies has enabled the application of NanoBRET to biological systems such as epigenetic protein–protein interactions, which have previously been challenging. By synergizing target engagement assays with more complex primary cell phenotypic assays, we have been able to demonstrate compound–target selectivity profiles to enhance cellular potency and offset potential liability risks. Additionally, we have shown that in the absence of a robust, cell phenotypic assay, it is possible to utilize NanoBRET target engagement assays to aid chemistry in progressing at a higher scale than would have otherwise been achievable. The NanoBRET target engagement assays utilized have further shown an excellent correlation with more reductionist biochemical and biophysical assay systems, clearly demonstrating the possibility of using such assay systems at scale, in tandem with, or in preference to, lower-throughput cell phenotypic approaches.
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Richard, Corentin, Myriam Benlaifaoui, Omar El Ouarzadi, Khoudia Diop, Antoine Desilets, Julie Malo, Wiam Belkaid, et al. "679 High fiber diet modifies gut microbiome, propionate production, intratumor immune response and is associated with outcome in patients with lung cancer treated with immune checkpoint inhibitors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A718. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0679.
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BackgroundThe gut microbiome plays a key role in immune checkpoint inhibitors (ICI) efficacy and several strategies are currently being investigated to improve microbiome composition. The impact of a specific diet on microbiome modulation and clinical outcomes remains unknown. In this study, we assessed the effects of a high fiber diet on clinical outcomes as well as on microbiome composition, production of fecal metabolites, and intratumor immune infiltration in metastatic non-small cell lung cancer (mNSCLC) patients amenable to ICI.MethodsIn this prospective study, 39 chemotherapy-refractory or naive patients with mNSCLC treated with ICI alone or in combination with chemotherapy completed a validated dietary survey. Based on the total fiber intake, patients were divided into high vs low fiber groups (HF vs LF). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between both groups. In addition, fecal and tumor samples were collected prior to ICI initiation. Fecal metagenomic sequencing was performed and fecal short-chain fatty acids (SCFA) were measured by LC-MS/MS. Tumoral transcriptome profiling was performed through RNA sequencing to define differentially expressed pathways.ResultsBaseline characteristics were well balanced between both groups, including body mass index (BMI) and PD-L1 status. Median PFS for the HF group was longer compared to the LF group (27.4 vs 12.6 months). Microbiome metagenomic profiling revealed higher baseline alpha diversity (p=0.048) in the HF group compared to the LF group. Bifidobacterium, Alistipes, and Bacteroides salyersiae were enriched in the HF group while Fusobacterium was overrepresented in the LF group. SCFA measurement revealed that a high level of propionate correlated with a significantly longer OS (not reached vs 18.4. months, p=0.02) in the entire cohort. Moreover, propionate levels were significantly higher in the HF vs LF group (p=0.02). At the tumor level, RNA sequencing demonstrated a downregulation of DNA repair mechanisms and an upregulation of humoral and adaptive immune responses in the HF group.ConclusionsIn this study, we demonstrated that a HF diet in patients with mNSCLC was associated with better clinical outcomes. Importantly, HF was associated with an enrichment of previously reported beneficial gut bacteria. Moreover, propionate correlated with longer OS and was increased in the HF group. This study provides further insights into how the diet can beneficially shift the microbiome composition and intratumor immune responses in patients with mNSCLC treated with ICI and this may lead to novel, dietary-geared therapeutic avenues in the oncomicrobiome arena.Ethics ApprovalThe study was approved by CRCHUM Institution,s Ethics Board, approval number 17.035.
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Papanikolaou, Xenofon, Adam Rosenthal, Rashid Z. Khan, Joshua Epstein, Christoph Heuck, Madhav V. Dhodapkar, Yogesh Jethava, et al. "Flow Cytometry Defined Cytoplasmic Immunoglobulin Index Is a Major Prognostic Factor for Progression of Asymptomatic Monoclonal Gammopathies to Clinical Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 2079. http://dx.doi.org/10.1182/blood.v124.21.2079.2079.
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Abstract Progression of Asymptomatic Monoclonal Gammopathies to Myeloma requiring treatment -Clinical Multiple Myeloma (CMM)- is an important issue in current clinical investigation toward secondary prevention, i.e. treating high-risk AMG. Several predictive models have been published, including one that incorporated gene expression profiling (GEP) of plasma cells (PC) where a GEP70 score ≥0.26 was linked to higher AMG-CMM progression in a multivariate model (Dhodapkar, Blood 2014). We have applied 2-parameter flow cytometry of DNA and cytoplasmic immunoglobulin (FDC) of bone marrow aspirates as part of baseline staging of all patients with plasma cell dyscrasia. A modification introduced in August 2006 on the doublet discrimination method increased accuracy and reproducibility of FDC results considerably and allowed for the detection of a plasma cell population with a low CI<2.8 as an independent predictor of PFS and OS in newly studies of newly diagnosed CMM treated with TT3b even in the context of GEP70 risk (Papanikolaou, ASH 2012). Realizing the importance of the FDC derived CI in CMM, we assessed whether FDC data from the observational AMG protocol S0120 could identify a population of patients with a high risk for progression to CMM. Out of 252 eligible patients, 130 had an FDC sample taken within 30 days prior to enrollment date and analyzed under the modified doublet discrimination method. FDC identified a light chain restricted population (LCR) in 121 patients. The number of distinct DNA stem lines in the flow cytometry assay, the percentage of LCR plasma cells (LCR%), their ploidy status and respective CI, were evaluated alone and in relation with clinical, laboratory and genetic parameters known to affect progression of AMG to CMM. For continuous FDC variables, the running log-rank statistics were used to determine the optimal cut-off points. In univariate analysis, the existence of at least two distinct DNA stem lines (HR: 3.3, P=0.002), a FDC LCR population of plasma cells >17% (HR: 6.76, P<0.001) and the presence of a LCR population with a CI<3.6 (HR: 6.42, P<0.001) (Figure 1) were statistically significant along with other clinical factors of established prognostic value. A M component> 3g/dL (HR: 12.5, P<0.001), an involved light chain level >10mg/dL (HR: 2.8, P=0.019), a GEP70 score ≥0.26 (HR: 8.22, P<0.001) and the presence of a LCR population with a CI < 3.6 (HR:4.15, P=0.002) survived in the multivariate analysis. To further confirm importance of a low CI to CMM progression, we compared the CI of S0120 with the TT3b patients. The CI was significantly lower in TT3b cases regardless of when the comparison was made for all patients or for strictly aneuploidy cases (P<0.0001) to exclude the possibility that the CI difference reflects the lower percentage of normal plasma cells found in CMM. In conclusion, FDC is an easily applicable, fast and low-cost test, which offers valuable prognostic information even in the era of gene expression profiling and other cytogenetic testing strategies. The identification of a low CI as a risk factor suggests that, progression of AMG to CMM is characterized by the emergence of a low immunoglobulin producing myeloma cell population. Figure 1: Time to progression requiring myeloma therapy by CI, S0120 Figure 1:. Time to progression requiring myeloma therapy by CI, S0120 Disclosures Heuck: Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Dhodapkar:Celgene: Research Funding. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.
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Liu, Caifei, Yingxin Shi, Jie Li, Xuewen Liu, Zhikai Xiahou, Zhongping Tan, Xing Chen, and Jing Li. "O-GlcNAcylation of myosin phosphatase targeting subunit 1 (MYPT1) dictates timely disjunction of centrosomes." Journal of Biological Chemistry 295, no. 21 (April 15, 2020): 7341–49. http://dx.doi.org/10.1074/jbc.ra119.012401.
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The role of O-linked N-acetylglucosamine (O-GlcNAc) modification in the cell cycle has been enigmatic. Previously, both O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) disruptions have been shown to derail the mitotic centrosome numbers, suggesting that mitotic O-GlcNAc oscillation needs to be in concert with mitotic progression to account for centrosome integrity. Here, using both chemical approaches and biological assays with HeLa cells, we attempted to address the underlying molecular mechanism and observed that incubation of the cells with the OGA inhibitor Thiamet-G strikingly elevates centrosomal distances, suggestive of premature centrosome disjunction. These aberrations could be overcome by inhibiting Polo-like kinase 1 (PLK1), a mitotic master kinase. PLK1 inactivation is modulated by the myosin phosphatase targeting subunit 1 (MYPT1)–protein phosphatase 1cβ (PP1cβ) complex. Interestingly, MYPT1 has been shown to be abundantly O-GlcNAcylated, and the modified residues have been detected in a recent O-GlcNAc–profiling screen utilizing chemoenzymatic labeling and bioorthogonal conjugation. We demonstrate here that MYPT1 is O-GlcNAcylated at Thr-577, Ser-585, Ser-589, and Ser-601, which antagonizes CDK1-dependent phosphorylation at Ser-473 and attenuates the association between MYPT1 and PLK1, thereby promoting PLK1 activity. We conclude that under high O-GlcNAc levels, PLK1 is untimely activated, conducive to inopportune centrosome separation and disruption of the cell cycle. We propose that too much O-GlcNAc is equally deleterious as too little O-GlcNAc, and a fine balance between the OGT/OGA duo is indispensable for successful mitotic divisions.
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Zhao, Z. "TET2 Loss Dysregulates the Behavior of Mesenchymal Stem Cells and Increases Their Ability to Promote TET2−/−-Driven Myeloid Malignancy Progression." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 222s. http://dx.doi.org/10.1200/jgo.18.90100.
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Background: TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cell (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. Aim: Tet2 loss may dysregulate the integrity of bone marrow niche, by which affects the malignant progression. Methods: Generation and maintenance of Tet2 conditional knockout MiceAnalysis of 5-hmC and 5-mC levels using dot blotFlow cytometry analysis, cell sorting, and hematopoietic progenitor cell (HPC) assayMSC Culture and long-term coculture with HSPCsReal-time PCR and RAN-Seq AnalysisMeDIP-seq to profile the genome-wide distribution of 5hmC. Results: Here, we show that while both Tet2 f/f ;Mx1Cre (conditional Tet2-inactivation in hematopoietic cells) and Tet2 f/f ;MxfCre (germ line Tet2-inactivation) developed myeloid malignancies in mice, Tet2 f/f ;MxfCre mice had a significantly shortened survival compared with Tet2 f/f ;Mx1Cre mice. Interestingly, Tet2 −/− recipient mice exhibited a higher incident of myeloid malignancies and a significantly reduced survival rate compare with WT recipient mice. These data indicate that Tet2 −/− bone marrow niche might promote the progression of myeloid malignancies in Tet2 −/− mice. Strikingly, deletion of Tet2 in mesenchymal stem cells (MSCs) using Prx1-cre is associated with a significantly accelerated malignancy progression and shortened survival, suggesting that MSCs are the cell components in Tet2 −/− mice play a role in the initiation/progression of Tet2 −/−-driven myeloid malignancies. Furthermore, Tet2 −/− MSCs displayed a significantly increased self-renewal, proliferating and differentiation capability as assayed by the frequency of CFU-F and commitment toward osteoblasts. In addition, Tet2 −/− but not WT MSCs exhibited a significantly increased supportive capacity to Tet2 −/− HSC/HPC proliferation. RNA-sequencing analysis revealed that Tet2 −/− MSCs exhibited a distinct gene expression profiles with 468 dysregulated genes as compared with WT MSCs. Furthermore, the number of 5-hmC peaks were significantly decreased in Tet2 −/− MSCs compared with WT MSCs based on whole genomic 5-hmC profiling. The majority of TET2-dependent 5hmC modifications in MSCs are located within genes. We then examined TET2 gene expression in MSCs derived from human myeloproliferative neoplasms (MPN) patients and healthy individuals and found that TET2 and 5-hmC was moderately down-regulated in MPN MSCs as compared with healthy controls. Conclusion: These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation, and provide evidence that dysregulation of epigenetic modifier in BMSCs contributes to the progression of myeloid malignancies.
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Yang, Jung-In, Taehoon Ha, Edward Zhou, Chris Tzanavaris, Craig E. Devoe, Xinhua Zhu, and Jeff Boyd. "Association of TP53 mutation status and GATA6 amplification with clinical outcome of pancreatic cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e16224-e16224. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16224.
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e16224 Background: Recent advances in pancreatic adenocarcinoma (PDAC) research unveiled that molecular subtypes reflect cancer prognosis and chemosensitivity. Here, we examined the possible use of genomic profiling of PDAC in the clinic by assessing retrospective clinical outcomes and treatment responsiveness based on genetic alterations. Methods: All patients treated for PDAC with Next-Generation Sequencing (NGS) data available between 2014 to 2020 at Northwell Health Cancer Institute were included in a retrospective analysis. Patients were subdivided into resectable and unresectable cancer. Genetic findings frequently reported in NGS were used to compare progression-free survival (PFS) and overall survival (OS) within subgroups. Survival probability was compared using Peto-Peto’s modified survival estimate followed by pairwise comparisons using Peto-Peto’s modified survival estimate. Family-wise error rate was adjusted using Benjamini & Hochberg method. Results: A total 115 patients were qualified for the evaluation. In all cases of PDAC, TP53 mutation (n = 89) was associated with poor OS compared to the wild-type TP53 gene (n = 19) (median OS 20.2 months, 95% CI 10.2 to 39.7, vs. 41.1 months, 95% CI 20.9 to 81.0, HR 1.98, p = 0.028). In unresectable PDAC, tumors with GATA6 amplification (n = 11) were associated with a significantly better OS over patients whose tumors harbored a TP53 mutation (n = 57) (median OS 22.9 months, 95% CI 9.6 to 54.5, vs. 10.0 months, 95% CI 4.2 to 23.8, HR 0.48, p = 0.048) . Within the TP53 mutation group, FOLFIRINOX (n = 21) did not show improved OS compare to Gem/NabP (n = 30) (mean OS 13.8 months, 95% CI 6.8 to 28.2, vs. 8.5 months, 95% CI 4.17 to 17.4, HR 0.84, p = 0.25). Other genetic alterations were not associated with OS. There was no difference in PFS in all PDACs. Conclusions: Our retrospective analysis showed that genetic changes in TP53 and GATA6 were significantly associated with the clinical outcome for PDAC. Mutation of TP53 was associated with poor OS in general. However, in unresectable PDAC, GATA6 amplification was associated with better clinical outcome than tumors with TP53 mutation. In contrary to general belief, FOLFIRINOX did not result in better OS than Gem/NabP.
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Dicitore, Alessandra, Maria Giulia Bacalini, Davide Saronni, Germano Gaudenzi, Maria Celeste Cantone, Giulia Gelmini, Elisa Stellaria Grassi, et al. "Role of Epigenetic Therapy in the Modulation of Tumor Growth and Migration in Human Castration-Resistant Prostate Cancer Cells with Neuroendocrine Differentiation." Neuroendocrinology 112, no. 6 (August 2, 2021): 580–94. http://dx.doi.org/10.1159/000518801.
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<b><i>Introduction:</i></b> Neuroendocrine transdifferentiation (NED) of prostate cancer (PC) cells is associated with the development of resistance to antiandrogen therapy and poor prognosis in patients with castration-resistant PC (CRPC). Many of the molecular events, involved in NED, appear to be mediated by epigenetic mechanisms. In this study, we evaluated the antitumor activity and epigenetic modulation of 2 epigenetic drugs, such as the demethylating agent 5-aza-2′-deoxycytidine (AZA) and the methyl donor S-adenosylmethionine (SAM), in 2 human CRPC cell lines with NED (DU-145 and PC-3). <b><i>Methods:</i></b> The effects of AZA and SAM on cell viability, cell cycle, apoptosis, migration, and genome-wide DNA methylation profiling have been evaluated. <b><i>Results:</i></b> Both drugs showed a prominent antitumor activity in DU-145 and PC-3 cells, through perturbation of cell cycle progression, induction of apoptosis, and inhibition of cell migration. AZA and SAM reversed NED in DU-145 and PC-3, respectively. Moreover, AZA treatment modified DNA methylation pattern in DU-145 cells, sustaining a pervasive hypomethylation of the genome, with a relevant effect on several pathways involved in the regulation of cell proliferation, apoptosis, and cell migration, in particular Wnt/β-catenin. <b><i>Conclusions:</i></b> A relevant antitumor activity of these epigenetic drugs on CRPC cell lines with NED opens a new scenario in the therapy of this lethal variant of PC.
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Wang, Juan, Haixia Guo, Cai Yun, Huiqin Chen, Liangchun Yang, Huihong Dou, Xin Tian, et al. "The Profiling of Circulating Tumor DNA in Pediatric Mature B-Cell Non-Hodgkin Lymphoma（B-NHL）: A Multicenter and Prospective Clinical Study." Blood 138, Supplement 1 (November 5, 2021): 2400. http://dx.doi.org/10.1182/blood-2021-151686.
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Abstract Background Next-generation sequencing (NGS) based on liquid biopsy has been an emerging technology to identify tumor-specific genetic aberrations in adult lymphoma. However, there were few studies on the genomic profiling of plasma circulating tumor-derived DNA (ctDNA) in pediatric mature B-NHL. Methods Paraffin-embedded tissue (FFPE) and plasma samples from the newly diagnosed patients were collected and sequenced by 475 genes panel before, during and post of treatment. Clinical stage system, risk stratification and treatment of pediatric mature B-NHL followed a the modified BFM-95 protocol. Results A total of 53 pediatric mature B-NHLs were enrolled，including 35 Burkitt lymphoma, 18 diffused large B cell lymphoma/high-grade B cell lymphoma (DLBCL/HGBCL). We collected 38 tissue and 124 plasma samples for somatic mutation testing. The number of somatic mutations and the TOP 5 genes detected in the 38 tissues and 31 baseline plasma samples, were 416 vs 496, and MYC(71%), DDX3X(45%)，ID3 (42%), TP53(40%), SMARCA4(29%) (Fig1. A)vs MYC(52%), DDX3X(45%)，ID3(42%), TP53(36%), GNA13(23%) (Fig1. B), respectively. The median allele frequency of mutations in plasma was 3%(ranged from 0.2% to 96.6%) and MYC, DDX3X, ID3, TP53, SMARCA4,ARID1A shows higher max somatic allele frequency (MSAF), indicated that was the early events in tumor genesis. The sensitivity of plasma ctDNA to detecting tissue mutations was 63.4% in the 19 matched samples (11 samples from BL and 8 samples from DLBCL/HGBCL) and the sensitivity in BL and DLBCL/HGBCL were 64.1% and 62%, respectively. All genomic alteration types, including single nucleotide variants (SNVs), indels, and gene fusions were detected in similar proportions in each sample type and the gene mutation rate of every gene detected in paired tissue and ctDNA samples. Among the 37 mature B-NHL patients, 6 patients were collected plasma samples after resection of tumor, of which 4 patients was not detected the somatic gene mutations in plasma (Fig. 2). The abundance of ctDNA in patients with stage IV (N=10) was significantly higher than that of stage I-II (N=6) (P=0.0002) and stage III patients(N=15)(P<0.0001)(Fig3. A). Similarly the abundance of ctDNA mutations in high risk patients(N =11)was significantly higher than that of low risk patients (N=8)(P<0.0001) and Medium risk patients (N=12) (P<0.0001) (Fig3. B). MSAF of ctDNA mutations was significantly correlated with LDH and the abundance of ctDNA mutations (P<0.0001) (Fig3. C,D). With a median follow-up of 182 Days, 33 patients have completed anti-tumor treatment, 27 patients completed post-treatment PET-CT, and 20 patients have done ctDNA testing synchronously. PET-CT showed tumor residue in 4 patients, of which 2 patients showed no tumor residue in pathology and ctDNA, 1 patient showed tumor residue in pathology but not in ctDNA and with tumor progression 6 months after treatment, 1 patient unable to take biopsy showed no tumor residue in ctDNA and was no tumor reccourence with regular follow-up. At the last follow-up, 1 patient was disease progression, and all of the 53 patients survived. Conclusion Plasma ctDNA testing by NGS was practicable in pediatric mature B-NHL. The abundance of ctDNA is significantly related to tumor burden. CtDNA testing may be more sensitive than PET-CT for residual disease assessment. Nevertheless, sample size expansion is required to verify such conclusions. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Demaree, Benjamin, Cyrille Delley, Cheryl Peretz, Harish Vasudevan, David Ruff, Aik Ooi, Catherine C. Smith, and Adam Abate. "Combined Single-Cell DNA Genotyping and Protein Quantification (DAb-seq) in Acute Myeloid Leukemias Reveals Distinct Immunophenotypic Subsets Among Pathogenic Clones." Blood 134, Supplement_1 (November 13, 2019): 2088. http://dx.doi.org/10.1182/blood-2019-127048.
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Genetic and immunophenotypic diversity is a hallmark of hematopoietic malignancies, and clonal evolution has been implicated as a driver of tumor initiation, progression, treatment response, and relapse. Consequently, a deeper understanding of the complex relationship between mutational profiles and disease phenotypes is critical to better understand the underlying disease processes. Probing the question of genotype-immunophenotype interplay at scale has historically proven difficult due to technical limitations permitting capture of only a single datatype from an individual cell. In acute myeloid leukemia (AML), flow cytometry for detection of measurable residual disease (MRD) has become standard of care for monitoring of treatment response and risk for relapse. At the same time, DNA-based molecular profiling of AML provides prognostic information and can guide therapeutic decisions at the time of diagnosis and disease progression. However, it remains a challenge to effectively integrate these assessments into a comprehensive model of disease state that can be used for clinical decision-making. Here we present DNA and Antibody sequencing (DAb-seq), a novel technology for simultaneously performing high-throughput, single-cell measurements of both DNA genotype and protein markers from >5,000 single cells. To our knowledge, DAb-seq is the first technology to directly integrate readouts of DNA genotype and cellular phenotype at the single-cell level. The experimental workflow leverages the single-cell microfluidic technology on the Mission Bio Tapestri platform, a system optimized to conduct multiplex single-cell targeted genomic DNA amplification. In our modified protocol, cells are stained with a pool of monoclonal antibodies conjugated with barcoded oligonucleotides, enabling a sequencing-based readout of single-cell protein signatures. The sequencing data is analyzed with a bioinformatic pipeline that separates antibody signal from targeted genotyping data on a cell-by-cell basis. We apply DAb-seq to the analysis of multiple AML patient samples, using a panel of 50 DNA targets comprising recurrently mutated genes in AML and 23 antibodies commonly used in flow cytometry-based MRD detection. In a single test case of pediatric AML, we identify cells harboring known pathogenic KRAS and FLT3 mutations at diagnosis and relapse. Among these genetically defined cell subsets, we observe differential protein expression of CD56, CD11b, and CD15. Specifically, we find a significant positive correlation between KRAS mutational status and combined expression of CD56 and CD11b. Similarly, FLT3 mutant cells, the dominant clone at relapse, are found to express elevated levels of CD15. We further apply DAb-seq technology to the profiling of mixed phenotype leukemia and monitoring the phenotypic dynamics of genetic clones in response to CD33 targeted therapy. Our data suggest cell populations defined by single variants in reality comprise multiple immunophenotypic subpopulations, underscoring the complex interplay between genotype and protein expression. While the precise mechanism underlying this immunophenotypic diversity remains to be elucidated, our work demonstrates the utility of DAb-seq in uncovering broader patterns of genotypic and phenotypic evolution in large AML patient cohorts. Ultimately, such studies could support further stratification of disease subtypes and increase the precision with which therapies are applied. Figure Disclosures Ruff: Mission Bio Inc.: Employment. Ooi:Mission Bio: Employment, Equity Ownership. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Abate:Mission Bio, Inc.: Equity Ownership.
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Herrera, Alex F., Samuel Tracy, Brandon Croft, Stephen Opat, Jill Ray, Lisa Musick, Joseph N. Paulson, Laurie H. Sehn, and Yanwen Jiang. "Risk Profiling of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients By Measuring Circulating Tumor DNA." Blood 136, Supplement 1 (November 5, 2020): 23–25. http://dx.doi.org/10.1182/blood-2020-136645.
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Introduction Early identification of patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) at high risk for treatment failure may allow for interventions to improve outcomes; however, known prognostic factors are inadequate. Circulating tumor DNA (ctDNA) has demonstrated the ability to identify previously untreated DLBCL pts at high risk of relapse (Kurtz et al. 2018). We assessed the potential for ctDNA to identify pts with R/R DLBCL receiving bendamustine and rituximab (BR) +/- polatuzumab (pola) at higher risk for disease progression. Methods GO29365 (NCT02257567) is a Phase Ib/II study comparing pola+BR versus BR in pts with transplant-ineligible R/R DLBCL and enrolled 80 pts (n=40 per randomized arm). The primary efficacy objective was independent review committee (IRC)-assessed complete response (CR) rate at primary response assessment (PRA, 6-8 weeks after Cycle 6, Day 1 or last dose of study drug). ctDNA was measured in available cohort samples using a customized DLBCL panel on a modified ctDNA CAPP-Seq workflow developed based on the prototype assay reported in Kurtz et al. 2018, with improvement of sensitivity and specificity. ctDNA was reported as mean mutant molecules per mL (MMPM). Plasma depleted whole blood from baseline was used as a source of germline DNA to filter non-tumor-specific variants. A total of 43 samples were available at baseline; eight pts without a paired germline were excluded from efficacy and correlative analyses. Of the 35 samples (n=21 Pola+BR; n=14 BR) with available germline data, paired samples were available for 25 pts at PRA. Detectable ctDNA (+/-) was determined using empirical p-values (<0.05) through a bootstrap algorithm (Newman et al. 2014, Pati et al. 2018). The proportions of pts with detectable ctDNA are reported by visit with 95% Clopper-Pearson binomial confidence intervals (CI). A Kruskal-Wallis test was used to compare ctDNA levels by response. Univariate and multivariate cox regression was used to correlate ctDNA levels with progression-free survival (PFS) and overall survival (OS). Results are reported descriptively without multiple testing correction. Results Intent-to-treat and biomarker evaluable populations were similar in demographics and efficacy, but there was a higher proportion of pola+BR versus BR pts assayed (60% vs 40%). Analyses are reported for the pooled arms, but results were consistent across both arms. ctDNA was detected in all available baseline (n=43) samples (95% CI: 92-100). Baseline ctDNA levels were correlated with known prognostic factors including International Prognostic Index (IPI), lactate dehydrogenase (LDH), Ann Arbor stage and number of prior therapies (Figure 1A). Higher ctDNA levels at baseline were negatively prognostic; when stratifying pts by median ctDNA levels the hazard ratio (HR) for PFS was 0.16 (95% CI: 0.07-0.41; Figure 1B); OS HR 0.23 (95% CI: 0.10-0.52). Similar results were observed for other quartile stratifications. This significant trend was maintained when adjusted in multivariate analysis for treatment, IPI >3, and LDH > upper limit of normal with an adjusted HR for PFS of 0.24 (95% CI: 0.07-0.81) and for OS an adjusted HR of 0.30 (95% CI: 0.09-0.97). Similar to the first-line setting (Kurtz et al. 2018), on-treatment log fold-changes in ctDNA trended with PRA response (Figure 1C); pts with a CR had a significantly greater average decrease in MMPM across timepoints than non-CR pts (Wilcoxon p-value <0.001). At PRA, four pts (three in pola+BR, one in BR) had cleared ctDNA, potentially due to treatment, all of which achieved CR. ctDNA was detectable in the remaining patients (n=25, 84%, 95% CI: 64-95). There was no clear trend between log fold reduction of ctDNA at PRA and PFS in this cohort, though this analysis is limited by sample size. Conclusions Baseline ctDNA levels were correlated with standard clinical risk factors, and were shown to have independent prognostic value for response, PFS and OS in R/R DLBCL pts treated with BR +/- pola. The degree of ctDNA change upon treatment was also correlated with response, but association with PFS needs further investigation with a larger sample size. This provides early evidence that ctDNA can be used to improve identification of R/R DLBCL pts at high risk for disease progression/relapse. Figure Disclosures Herrera: AstraZeneca: Research Funding; Karyopharm: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Tracy:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Croft:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Opat:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ray:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Musick:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Roche/Genentech, Inc.: Current Employment. Paulson:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Sehn:Chugai: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria. Jiang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment.
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Liu, Bin, Aaron Lisberg, Ramin Salehi-Rad, Jay Lee, Linh M. Tran, Kostyantyn Krysan, Raymond Lim, et al. "Abstract CT219: Phase I trial of in situ vaccination with autologous CCL21 gene-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced non-small cell lung cancer (NSCLC)." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT219. http://dx.doi.org/10.1158/1538-7445.am2022-ct219.
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Abstract Background: Although immune checkpoint blockade (ICB) targeting Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) alone or in combination with chemotherapy is now a first-line option for patients with advanced NSCLC, the majority of patients do not benefit from anti-PD-1/PD-L1 monotherapy, and the combination with chemotherapy is often associated with toxicity. For patients who initially respond to PD-1/PD-L1 inhibition, many relapse after an initial response and are in need for innovative strategies to overcome the resistance to ICB. One possible approach is to utilize in situ vaccination with functional chemokine gene-modified antigen presenting cells (APCs) that take advantage of the full repertoire of tumor antigens in the tumor microenvironment (TME) in order to restore tumor antigen presentation, promote tumor infiltration of immune cells driven by chemokine gradient, and facilitate tumor-specific T cell activation, both locally and systemically. The chemokine CCL21 is a therapeutic candidate due to its ability to promote infiltration and co-localization of naïve T cells and antigen-experienced dendritic cells (DCs) and facilitate T cell activation. In preclinical studies as well as a phase I clinical trial, we observed that intratumoral (IT) injection of CCL21-DC induces the infiltration of autologous DC and T cells into the TME, and generates systemic tumor-specific immune responses against multiple tumor antigens. We also observed tumoral PD-L1 upregulation following CCL21-DC injection, which may hinder T cell function. Similarly, the lack of efficacy of PD-1/PD-L1 inhibitors could potentially be combated by enhanced T cell infiltration and augmented APC function in the TME following in situ vaccination with CCL21-DC. Therefore, we are currently evaluating the safety and efficacy of combining IT CCL21-DC and intravenous (IV) pembrolizumab in advanced NSCLC patients following progression on ICB or tyrosine kinase inhibitor (TKI) therapy in a phase I trial (NCT03546361). Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or EGFR/ALK mutant after progression on TKI. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and immune monitoring studies. [B.L. and A.L. contributed equally to this work as first authors.] Citation Format: Bin Liu, Aaron Lisberg, Ramin Salehi-Rad, Jay Lee, Linh M. Tran, Kostyantyn Krysan, Raymond Lim, Camelia Dumitras, Zhe Jing, Michael Oh, Fereidoun Abtin, Robert Suh, Scott Genshaft, Scott Oh, Gregory Fishbein, Ciara M. O'Higgins, Anita Kaul, Kanwarpal Kahlon, Shahryar Ashouri, Jonathan Goldman, David Elashoff, Edward Garon, Steven Dubinett. Phase I trial of in situ vaccination with autologous CCL21 gene-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT219.
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Johann, Donald, Pingping Qu, Rachael Sexton, Antje Hoering, Joshua Epstein, Shmuel Yaccoby, Frits van Rhee, Saad Z. Usmani, John Crowley, and Bart Barlogie. "Gene Expression Profiling (GEP) of Whole Bone Marrow Biopsies (BMB) in Multiple Myeloma (MM) – Relationship to Plasma-Cell (PC)-Based GEP-Defined Risk and Molecular Subgroups." Blood 120, no. 21 (November 16, 2012): 3953. http://dx.doi.org/10.1182/blood.v120.21.3953.3953.
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Abstract Abstract 3953 PC-GEP provides great insight into MM heterogeneity as defined by 7 distinct molecular subgroups, along with clinical correlates and prognosis, as identified by the GEP-70 model. As is now increasingly appreciated in MM, a close interaction exists between PC and the bone marrow micro-environment (ME), which results not only in MM bone disease but also contributes to MM progression and drug resistance. We postulated that such interaction could be revealed by performing GEP both on PC and the bone marrow biopsy (BMB) proper. In addition to having demonstrated that BMB-GEP can attain a normal (NL)-like status in comparison with NL donors with favorable prognostic implications, we are now reporting on paired comparisons of BMB-GEP and PC-GEP toward elucidating whether different molecular subgroups (MOLS) (namely, CD-1, CD-2, MAF, MAF-B, MS, HY, PR) and GEP-70-defined prognostic risk groups (RISK) engage the ME differentially. Toward this end, a recently defined BMB-GEP model of 65 genes, distinguishing NL, MGUS/AMM, MM and MM-CR, was applied to determine whether linkage existed to MOLS and RISK. Indeed, based on mean-based statistics, BMB-65 scores varied among MOLS and RISK (both p=0.013). A negative correlation (R=-0.204) existed between BMB-65 and PC-70 scores (p=0.0014). Further analysis within MOLS revealed significant negative correlations within MF (R=-0.57, p=0.0087) and MS subtypes (R=-0.33, p=0.037). None of the other MOLS showed any significant correlations. This is the first demonstration in patient MM samples that MOLS may engage the ME differentially. The more pronounced inverse correlations of MF and MS subtypes reveal a counter-relationship between RISK and BMB-65 score. This implies that with greater aggressiveness of PC, the BMB appears less NL-like, and is thus more modified to support the malignant PC processes. More detailed analyses will be presented in the context of other GEP and clinical parameters, specifically concerning the prognostic implications of BMB scores at baseline. Correlation between GEP70 score and BMBX 65-gene score within each molecular subgroup Molecular Subgroup N Correlation of GEP70 risk and BMBX 65-gene score P value for testing no correlation CD-1 15 −0.39 0.1494 CD-2 39 −0.22 0.1747 HY 71 −0.15 0.1931 LB 33 0.12 0.4927 MF 20 −0.57 0.0087 MS 40 −0.33 0.0368 PR 25 −0.13 0.55 Overall 243 −0.204 0.001373 Disclosures: No relevant conflicts of interest to declare.
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Ho, Christine M., Theresa Hahn, Paul K. Wallace, Yali Zhang, Ahmad Fora, George L. Chen, Sarah A. Holstein, et al. "Identification of Immune Phenotypes Associated with Improved Progression Free and Overall Survival for Patients with Multiple Myeloma Treated with Autologous Hematopoietic Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 3454. http://dx.doi.org/10.1182/blood.v128.22.3454.3454.
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Abstract The treatment of transplant-eligible multiple myeloma (MM) patients usually consists of induction therapy followed by autologous hematopoietic cell transplant (AHCT). Many patients relapse or have disease progression post-AHCT, however selected patients will maintain long term disease control. In addition to standard prognostic features, we investigated whether immune phenotypes predict progression and/or long term disease control after AHCT. In a cohort of 101 MM patients who received high dose melphalan with AHCT between 8/2007 and 9/2014, we performed a comprehensive peripheral blood immunophenotyping panel including 35 T-, B-, NK- and Dendritic Cell (DC) subsets at a median of 25 days pre-ASCT and at day +100 post-ASCT. The immunophenotyping panel included total numbers of T cells (CD3+, CD4+, CD8+), B cells (CD19+, CD20+), NK cells (CD56+CD16+) and myeloid (CD11c+) and plasmacytoid (CD123+) dendritic cells. T cell subsets included the relative proportions of double positive (CD3+CD4+CD8+), double negative (CD3+CD4-CD8-), CD4+ and CD8+ Naïve (CD3+ CD45RA+ CD45RO- CD27+), CD4+ and CD8+ central memory (CD3+ CD45RA- CD45RO+ CD27+), CD4+ and CD8+ effector memory (CD3+ CD45RA- CD45RO+ CD27-), recent thymic emigrants (CD3+ CD4+ CD45RA+ CD31+), and T-regulatory cells (CD3+ CD4+ CD25(br), CD3+CD4+CD25+CD127(d), CD3+CD4+CD25+CD127-HLADr+). B cell subsets included proportions of naïve (CD19+ CD27-), and memory (CD19+ CD27+, pre-switch CD19+ IgD+ CD27+, post-switch CD19+ IgD- CD27) cells. We also performed limited immune profiling on the apheresis product which included T-cell subsets (CD3+, CD4+, CD8+, double positive (CD3+CD4+CD8+), double negative (CD3+CD4-CD8-) cells) and NK cells (CD16+CD56+). All patients survived to day +100. We examined MM response to AHCT, recovery of absolute lymphocyte count (ALC) by day +15 post-AHCT, PFS and OS. Characteristics in 101 patients pre-AHCT were: median (range) age 60 (28-75) yrs; 55% female; 29% KPS ≥90; response to most recent therapy was 16% in CR/sCR, 39% in VGPR, 37% in PR, 9% <PR. MM responses at day + 100 included: 44% achieved or maintained CR/sCR, 23% VGPR, 7% PR, and 5% progressed. The peripheral blood immune profile was not representative of the apheresis product immune profile. Also, immune profiling in the apheresis product did not significantly correlate with day +100 peripheral blood immune profiles or PFS/OS. Achievement of CR/sCR at day +100 post-AHCT was not associated with any peripheral blood immunophenotypes tested at either pre-AHCT or day +100 post-AHCT. ALC recovery by day +15 post-AHCT was not associated with significantly longer median PFS or OS than those who did not recover ALC by day +15, in contrast to prior reports. Improved 2-year PFS and OS correlated with select pre-AHCT peripheral blood B cell populations. Elevated pre-AHCT total CD19+ B cell count was significantly associated with improved 2 year PFS (53% for the lowest (<25%) quartile, 59% for middle quartiles (25-75%), and 83% for the upper (>75%) quartile (P=0.01)) and OS (Figure 1). In addition, increased CD20+ B cell count and increased naïve and memory B cells counts were associated with improved PFS/OS. Higher day +100 post-AHCT gamma/delta T cell absolute count correlated with improved 2 year PFS: 45% for the lowest (<25%) quartile and 65% for highest (≥25%) quartiles (P=0.02), and OS (see Figure 2). Elevated day +100 AHCT absolute CD4+ central memory cell counts were associated with OS (Figure 3), but not with PFS. We demonstrate that select subsets of B cell and T cell populations at day +100 post-AHCT correlate with PFS and OS. We are investigating whether these phenotypic changes directly correlate with PFS/OS or are associated with an intermediate event or treatment. Additional studies are planned to examine whether these changes are associated with individual, innate patient immune characteristics or if an individual patient's immune system may be modified to express these favorable immune phenotypes. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. Holstein:Millennium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Sanchez-Guijo, Fermin M., Eva Lumbreras, Patricia Morais, Juan-Luis Garcia, Norma C. Gutierrez, J. F. San Miguel, Consuelo del Canizo, and Jesus M. Hernandez-Rivas. "Imatinib Mesilate Modifies Genes Involved in Hematopoiesis in Non Clonal Bone Marrow Cells from CML Patients in Complete Cytogenetic Response." Blood 110, no. 11 (November 16, 2007): 2947. http://dx.doi.org/10.1182/blood.v110.11.2947.2947.
Full textAbstract:
Abstract Imatinib mesilate (IM) is the standard treatment for newly diagnosed patients with chronic phase (CP) CML. Bcr-Abl signaling has a wide range of biological activities, mainly mediated through activation of Ras/mitogen-activated protein kinase (MAPK) pathways, with broad effects on changes in cell adhesion (through Rho), proliferation (MAPK pathway) and apoptosis (through Akt). IM’s efficacy results from a blockade of these effects. Extensive work on the gene-expression profiling of CML cell lines under IM therapy has been published in order to predict disease transformation or IM resistance. Nevertheless, information on the effects of IM on the residual non clonal bone marrow (BM) hematopoietic compartment is scarce, and this is an important issue, since most responding patients will require long term treatment with IM. Therefore, in the present work we have assessed the gene expression profile (GEP) of whole BM hematopoietic cells from 20 patients with CP-CML in CCR after 6 to 12 months on IM therapy and compared it with that of 6 normal BM donors. Total RNA (100-500 ng) was amplified and labeled using the “GeneChip Two-Cycle cDNA Synthesis Kit” and hybridized to “Human Genome U133A” microarray (Affymetrix). Processing of genechip data was carried out using the Robust Multi-chip Average (RMA) and the Affymetrix Microarray Suite v.5 (MAS5) gene expression algorithms. The Significance Analysis of Microarrays (SAM) algorithm identified gene expression changes in a total of 490 genes (125 up and 365 down-regulated) when samples from CCR CML patients were compared to normal BM samples. Differential genes were grouped in 4 different areas, based on their function: proliferation, apoptosis, ubiquitination and adhesion. In CCR CML samples, there was a lower expression of genes involved in cell proliferation (e.g. C6ORF108, CENPE, CENP5, ESPL1 or GAS6) and cell cycle progression (e.g. PLCB1, ZW10, CUL4A or FOSB). There was an upregulation of genes involved in the induction of apoptosis (e.g. CDC2L2, FOXO3A, ING2, ING3, RYBP or TNFRSF1B) and in the ubiquitination of proteins (e.g. ARIH1, FBXW7, RKHD2, RNF7, SUMO1, UBA2 or UBE2W). Regarding cell-to-cell adhesion, several genes involved in this processes were downregulated (e.g. ITGBL1, CTNNA1, PCDHGA1, TROAP, FLOT2, IGSF4B, SELP, SIGLEC6, ADAM22 and STAB1). In addition, in all CML samples the erythropoietin receptor (Epo-R) gene was downregulated. This is of interest since many patients on IM therapy display a slightly low Hb level, regardless of circulating Epo levels. In summary, IM induces a decrease in proliferation and increase in apoptosis and ubiquitination in residual non clonal BM cells from CCR CML patients. In addition, IM diminishes cell-to-cell adhesion and downregulates the expression of the Epo receptor in the hematopoietic compartment of these patients.
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Khan, Uqba, Talia Biran, Allyson J. Ocean, Elizabeta C. Popa, Joseph T. Ruggiero, Doru Paul, Chelsea Garcia, et al. "Phase II study of a telomerase-specific oncolytic adenovirus (OBP-301, Telomelysin) in combination with pembrolizumab in gastric and gastroesophageal junction adenocarcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4145. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4145.
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TPS4145 Background: Although checkpoint inhibitors (CPIs) can produce durable responses in gastric cancer patients (pts) in the 3rd line setting, the response rate is only 10-15%. Therefore, there is a huge unmet need to enhance the response rate of CPIs to provide benefit to wide range of pts. A novel concept in immuno-oncology is the use of cancer specific oncolytic viral therapy. In addition to the specific killing of the tumor by the virus, these agents can induce an immunogenic cell death in the tumor to augment the immune activation driven by PD-1 inhibition. OBP-301 is an oncolytic adenovirus genetically modified to be able to selectively replicate in cancer cells by introducing human telomerase reverse transcriptase (hTERT) promoter. Results of a phase I study of OBP-301 in solid tumor pts demonstrated the safety and efficacy of intra-tumoral injection of OBP-301. A pre-clinical study of the combination of OBP-301 with anti-PD-1 antibody has also shown significant synergistic activity as well. Based on these encouraging pre-clinical and clinical data, we designed a phase II clinical trial to examine the safety and efficacy of combination of pembrolizumab and OBP-301 in the treatment of PD-L1 positive metastatic gastric/GEJ adenocarcinoma. Methods: This is a multicenter, non-randomized phase II trial of OBP-301 with pembrolizumab in metastatic gastric/GEJ adenocarcinoma that has progressed on at least 2 lines of prior therapy. Eligibility criteria include PD-L1 positive tumors as defined by a combined positive score, performance status ≤1, and good end organ function. The primary endpoints are to examine objective response rate and safety of OBP-301 with pembrolizumab. The secondary endpoints are to examine disease control rate, duration of response, overall survival and progression free survival. Correlative studies are planned to identify biomarkers for response to combination therapy by using multiparameter flowcytometry, single-cell transcriptional profiling and immunohistochemistry. All eligible pts will receive 1x1012Viral Particles/mL of OBP-301 administered every 2 weeks for total of 4 injections, injected directly into tumor via upper endoscopy. Every pt will also receive pembrolizumab 200 mg IV every 3 weeks for 2 years or until progression. Pts will be enrolled in a Simon two stage design, with 18 pts in the first stage. If 3 or more pts respond to the combination therapy, the study will move forward to stage 2, with 19 more pts enrolled. The study is currently enrolling pts.
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Papaioannou, Dimitrios, Andreas Petri, Charlotte Albæk Thrue, Stefano Volinia, Karl Kroll, Yan Pearlly, Ralf Bundschuh, et al. "HOXB-AS3 Regulates Cell Cycle Progression and Interacts with the Drosophila Splicing Human Behavior (DSHB) Complex in NPM1-Mutated Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 1514. http://dx.doi.org/10.1182/blood.v128.22.1514.1514.
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Abstract Background:The expression and prognostic significance of long non-coding RNAs (lncRNAs) in older (≥60 years) patients with cytogenetically normal acute myeloid leukemia (CN-AML) has recently been reported (Garzon et al, 2014). Among the top up-regulated lncRNAs in NPM1-mutated (NPM1mut) CN-AML, the lncRNA HOXB-AS3 wasidentified. As aberrant expression of HOX genes is associated with NPM1mut AML and HOX-related lncRNAs have been reported to regulate HOX genes (e.g. HOTAIR), we hypothesized that HOXB-AS3 could have a functional role in this disease setting. Methods:HOXB-AS3 expression profiling was performed by qRT-PCR in AML cell lines (Kasumi-1, KG1a, MOLM-13, MV-4-11, OCI-AML3 and THP-1), 12 primary CN-AML patient samples (NPM1mut=6, NPM1-wild-type (WT)=6) and mononuclear cells from healthy donors (n=6). Correlation analysis of mRNA/lncRNA expression was performed using Spearman analysis in 71 older CN-AML patients, profiled by RNA-sequencing. Knock-down (KD) of HOXB-AS3 was performed in vitro (Amaxa-nucleoporation) and in vivo (in a patient-derived xenograft (PDX) model) using LNA-modified gapmers. Comparative proteomic analysis was conducted by applying a modified version of the RNA antisense purification (RAP) protocol (McHugh et al, 2015). Results:Of the cell lines tested, only OCI-AML3, which harborsmutated NPM1, showed high levels of HOXB-AS3 expression. Five- and 3-prime RACE assays identified 3 previously annotated (NR_033201/NR_033203/ENST000491264) and 1 novel variant of HOXB-AS3 in OCI-AML3 cells. NPM1 mutated patient samples exhibited higher expression of HOXB-AS3 in comparison to those with WT NPM1 (P<.01) and healthy donors (P<.01). To gain insights into the function of HOXB-AS3, we derived a HOXB-AS3-related mRNA expression signature; 154 mRNA transcripts correlated positively and 122 correlated negatively with high HOXB-AS3 expression. Gene ontology analysis revealed enrichment of genes involved in the pathway of DNA repair (P<.01) in patients with high HOXB-AS3 expression. To assess the functional impact of HOXB-AS3, HOXB-AS3 KD studies using LNA gapmers were performed. In vitro KD of HOXB-AS3 led to decreased proliferation of OCI-AML3 cells, as measured by BrdU-based cell cycle analysis (S-phase average % in control v KD: 24% v 16%, P=.02). HOXB-AS3 KD also led to a reduction in the number of formed colonies by OCI-AML3 cells (P<.01), whereas it had no significant effect on apoptosis. HOXB-AS3 KD in primary NPM1mut AML samples (n=3) led to a decrease in colony formation (P<.01). Gene set enrichment analysisperformed in HOXB-AS3 silenced OCI-AML3 cells (profiled by RNAseq) revealed activation of the DNA damage response pathway in the HOXB-AS3 expressing cells. To assess the in vivo effects of HOXB-AS3 KD,we treated 10 NSG mice transplanted with the blasts of a NPM1mut AML patient with nanoparticle-formulated anti-HOXB-AS3 gapmers or control gapmers. We obtained RNA after 7 days of treatment and confirmed HOXB-AS3 KD in human cells (P<.01). Survival analysis is currently ongoing but when we compared the leukemia burden at 3- and 6-weeks post-transplant in mice with adequate leukemia engraftment (>30% human CD45+ cells) the percentage of circulating blasts decreased in HOXB-AS3-KD (from 43% to 30%), while it increased in controls (from 36.5% to 62.8%). Last, to identify potential HOXB-AS3-binding proteins we performed RAP experiments in OCI-AML3 cells. HOXB-AS3- and U1-specificRNA-protein complexes were isolated by hybridization with biotinylated probes. Mass spectrometry and comparative analysis of theeluates yielded 22 candidate HOXB-AS3-interacting RNA-binding proteins. These included the core components of the DSHB complex (SFPQ and NONO). RNA-immunoprecipitation experiments validated the interaction of HOXB-AS3 with NONO. The DSHB complex is a major mediator of the DNA damage response and experiments that will elucidate the importance of HOXB-AS3 interaction with NONO in this context are underway. Conclusions: HOXB-AS3 is highly expressed in NPM1mut CN-AML and regulates cell cycle progression of AML blasts. HOXB-AS3 KD decreases cell proliferation and colony formation capacity of leukemia cells in vitro. HOXB-AS3 KD also decreases leukemia burden in an in vivo PDX model. Comparative proteomic analyses identified several binding partners of HOXB-AS3, such as the DSHB complex, which is a key mediator of the DNA repair process. Disclosures No relevant conflicts of interest to declare.
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de Souza, J. A., C. Wei, S. Noguchi, K. Lu, H. Ishihara, D. Aoki, and N. T. Ueno. "Cyclin-dependent kinase (CDK) activity as a prognostic marker in primary epithelial ovarian cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 5575. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5575.
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5575 Background: The unpredictable nature of primary epithelial ovarian cancer (EOC) response to treatment necessitates the identification of factors that predict long-term outcome. CDK activity is the core regulator of the cell-cycle checkpoint for cancer cells. We previously found that cell death induced by taxanes requires increased activity of CDK1 and CDK2- fundamental kinases in cell proliferation. Thus, we hypothesized that CDK1/2 activities can determine the prognosis of patients with primary EOC. Methods: We retrospectively analyzed frozen ovarian cancer specimens from 72 women treated with cytoreductive surgery and adjuvant chemotherapy for newly diagnosed EOC. Median patient age was 61 years (range, 38–80), 91% had FIGO stage III/IV disease, and 86% were treated with platinum- or taxane-based regimens. Median follow-up was 32 months; median time to treatment failure (TTF), defined as time from surgery to first relapse for patients who had achieved complete response or time to disease progression for those who had persistent disease, was 15 months. Enzymatic activity of CDK1/2 in the tumor tissues was determined by a modified in vitro kinase activity assay using a C2P device (Sysmex Inc.). Recursive partitioning and regression trees algorithm (RPART) was used to identify the cohorts based on CDK1/2 activities. Results: In the univariate analysis, disease stage (p=0.021), type of surgery (optimal vs. suboptimal) (p=0.004), presence of ascites (p=0.043), and CA125 after the adjuvant therapy (p=0.005) were significant predictors of TTF. The cohort with CDK2 activity = 87.3 had a significantly shorter TTF (p=0.014) and the cohort with CDK1 activity = 226.35 showed a trend toward longer TTF (p=0.094). Multivariate Cox proportional hazards regression analysis revealed CDK2 activity (<87.3 vs. = 87.3) (p=0.012) and CA125 level at completion of the adjuvant chemotherapy regimen (p=0.02) to be independent predictors of TTF. Conclusion: Our data supports kinase activity of cell cycle as a clinically significant prognostic factor. To extend these findings, we plan to conduct a large prospective study to determine whether CDK1/2 profiling can predict long-term outcome in primary EOC. [Table: see text]
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Fong, Jerry, John R. Edwards, Jacob R. Gardner, Amanda F. Cashen, Kilian Q. Weinberger, and Jacqueline E. Payton. "A Novel Method to Identify Epigenetic Subclones with Increased Fitness from Genomic DNA Methylation Data of Lymphoma and Leukemia Patients." Blood 132, Supplement 1 (November 29, 2018): 2604. http://dx.doi.org/10.1182/blood-2018-99-111057.
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Abstract DNA methylation has been functionally implicated in X-inactivation, genomic imprinting, and silencing of transposable elements. DNA methylation also has a complex regulatory relationship with gene expression. Canonically, methylation around the promoters of tumor-suppressor genes induces gene-silencing, thereby representing a hit in the two-hit hypothesis for the development of cancer. Unfortunately, profiling studies conducted to determine how aberrant methylation may contribute to cancer progression are confounded by heterogeneity in the original clinical sample. Thus, though studies in patients with Acute Myeloid Leukemia (AML), Diffuse Large B-cell Lymphoma (DLBCL), and Chronic Lymphocytic Leukemia (CLL) have found that variation in detected methylation values from patients at diagnosis correlates with prognosis following therapy, they do not address which subclonal methylation events contribute to cancer progression. To address this concern, we developed a novel computational method to deconvolve the bisulfite sequencing data from a sample into its major methylation profiles and their respective prevalence in the sample. Our method, based on a modified Hidden Markov Model, effectively models the autocorrelations found in methylation data and outperforms existing algorithms. Our method was validated across a wide range of mixture simulations, where bisulfite sequencing reads from various different cell types were subsampled to form test samples that could be deconvolved. We were able to accurately (98%) distinguish distinct methylation patterns corresponding to the expected underlying subpopulations, such as for CD14 and CD22 in mixtures of germinal center B-cells and monocytes and for CD4 and CD8A in mixtures of CD4+ T-lymphocytes and CD8+ T-lymphocytes. These patterns also recapitulated differentially methylated regions (DMRs) identified by an independent DMR-caller. Given that our method does not rely on cell-type specific parameters and is therefore robust to all samples, to further validate and demonstrate the applicability of our method, we conducted Agilent Methyl-Seq on 5 primary DLBCL samples procured by the Lymphoma Core at the Siteman Cancer Center. As a positive control, our method identified differential methylation profiles at loci expected to differ from underlying CD19+ and CD4+ cells, which comprise a large majority of each sample. Our method also identified distinct methylation profiles not found in reference profiles from normal cell-types, suggesting these methylation profiles may be specific to DLBCL. To further validate these findings, we used single-cell bisulfite-sequencing at ten loci to demonstrate that the methylation profiles predicted by our method from the original sample are found in individual cells. We found several methylation patterns that only existed in a subset of CD19+ cells, which may represent distinct epigenetic subclones of DLBCL. Using our novel computational method, we next profiled the subclonal epigenetic architecture of publicly available (dbGaP) paired samples from patients with AML (n=137) at diagnosis and following therapy. We were able to not only identify subclonal methylation profiles that were specific to cancer but also find profiles at higher prevalence in patients at relapse compared to diagnosis. These methylation profiles, which were enriched for genes in cancer pathways as seen by Gene Set Enrichment Analysis, may confer fitness advantages for a cancer subclone to expand. We are currently conducting additional analyses to characterize the epigenetic regulatory circuits that contribute to our observed increase in subclonal fitness. In summary, we have developed a robust method to identify subclonal methylation changes that may contribute to cancer progression and prognosis, as seen in AML, and may lead to new avenues for improving treatment for patients with leukemia or lymphoma. Disclosures No relevant conflicts of interest to declare.
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Vaid, Ashok K., Suman S. Karanth, Aseem Khurana, Nitin Sood, Ashok Sen, Gautam Dheeraj, Bhuvan Chugh, and Saurabh Mishra. "Differences in the Clinicopathological Feature, Prognostic Features and Treatment Outcomes between Molecular Subtypes Among Indian Cohort with Diffuse Large B-Cell Lymphoma - a Single Center Experience." Blood 134, Supplement_1 (November 13, 2019): 5350. http://dx.doi.org/10.1182/blood-2019-126414.
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Background: Diffuse Large B cell Lymphoma (DLBCL) accounts for nearly 25% of all Non-Hodgkin's lymphoma (NHL) in the developed world, making it the most common lymphoma. With the diversities in clinical presentation, morphology, molecular and genetic alterations, DLBCL represents a heterogeneous group rather than a single disease entity. Based on the cell-of-origin (COO) concept, gene expression profiling (GEP) has identified two major subtypes of DLBCL with differing prognoses. We aim to study the trends in the clinico-pathological features, prognostic factors and treatment outcomes following standard therapy between the molecular subtypes. Methods: A prospective study with 243 consecutively diagnosed cases of DLBCL between September 2009 and April 2017 were included. The clinico-pathological features, IPI score, extranodal involvement and stage of disease were recorded using a predesigned proforma. All patients received Rituximab based treatment which was modified according to their tolerability. Molecular subtyping to GCB and ABC subtype was performed using immunohistochemistry.Primary objective was to assess the clinico-pathological features, prognostic factors and differences between the molecular subtypes in Indian population. Secondary objective was to study the overall progression free survival (PFS). Results: Out of 243 patients enrolled in the study, 47% (n=129) were > 60 years, the median age being 55 years. Majority were males (63%). Fever (28%), pain abdomen (11%), weight loss (30%) and painless neck swelling (26%) were the most common symptoms. Nodal presentation was more common than extranodal [56.4% (n=137) versus 43.7% (n=106) respectively]; stomach (12.2%) being the most common extranodal site. 22.6%(n=55) high intermediate and 38.3% (n=93) with high IPI score. Bone marrow involvement was detected in 23% population (n=56). 51% (n=124) were diagnosed as stage IV, 24.3% (n=59) stage III, 16% (n=39) stage II and 8.6% (n=21) in stage I. Molecular subtyping was performed in 198 patients (81.4%) with GCB subtype seen in 45.5% (n=90) and ABC in 54.5% (n=108). 62.6% achieved complete metabolic response (CMR) and 18.9% (n=39) had disease progression. ABC subtype had more extranodal presentation [(54.6%, n=59 v/s 35.6%, n=32); p=0.007]. More number of disease progressions [17.8%; n=18 v/s 10.1%, n=9] and deaths [11.9%; n=12 v/s 3.4%, n=3]; p=0.046 were recorded in ABC Subtype. High IPI Score was seen in ABC subtype [45.6%, n=47 v/s 28.1% [n=25], p=0.063. Median survival time of patients was 81 months + SE 1.705 [CI 72.26-78.95]. There was a significant difference in the median PFS among those whose did not progress versus those who did [87.22 months v/s 72.66 months]. ABC subtype, high LDH Levels > 618 and patients with higher stage at presentation had disease progression. In this study, using both univariate and multivariate cox regression model, no risk factor was found to be associated with survival. Conclusions: R-CHOP remains the standard of care for patients with DLBCL. However, literature reports a cure rate of only 60% with standard immuno-chemotherapy with 40% eventually dying of the relapsed disease. DLBCL can no longer be considered and treated as one disease. It is imperative to identify those molecular and prognostic markers that would identify subset of patients who would benefit from a more aggressive course. Disclosures No relevant conflicts of interest to declare.
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Avigdor, Abraham, Pierre Peterlin, Junichiro Yuda, Mor Tal Moskovitz, Nashat Y. Gabrail, Yakir Moshe, Bruno Quesnel, et al. "Phase 1 first-in-human study of ABBV-184 monotherapy in adult patients with previously treated acute myeloid leukemia or non-small cell lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS2674. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps2674.
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TPS2674 Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive therapeutic target in cancer, due to its broad expression in solid tumors and hematologic malignancies but limited expression in normal tissues. Elevated survivin expression is associated with an increased invasive phenotype and worse clinical outcomes. ABBV-184 is a first-in-class T-cell receptor (TCR)/anti-cluster of differentiation 3 (CD3) bispecific molecule. It is composed of a soluble TCR that binds to a survivin-derived peptide bound to the class I MHC allele HLA-A2:01 expressed on tumor cells and to the CD3 receptor on T cells. Preclinical data have demonstrated that treatment with ABBV-184 results in T-cell activation, proliferation, and redirected cytotoxicity of HLA-A2:01–positive target cell lines. This first-in-human trial evaluates ABBV-184 monotherapy in patients with previously treated acute myeloid leukemia (AML) or non-small cell lung cancer (NSCLC). Methods: Patients (≥18 years, Eastern Cooperative Oncology Group performance status ≤2, HLA-A2:01 restricted genotype) with relapsed or refractory AML or NSCLC are currently enrolling in this phase 1 multicenter, open-label trial (NCT04272203), which includes parallel dose-escalation and dose-expansion phases for both diseases. Primary objectives are to determine the recommended phase 2 dose (RP2D) of ABBV-184 (dose escalation) and to assess its preliminary efficacy (dose expansion). Secondary objectives include safety, tolerability, pharmacokinetics (PK), and immunogenicity assessments (dose escalation and dose expansion) and duration of response (dose expansion). Patients will receive intravenous infusion of ABBV-184 once weekly. Dose escalation of ABBV-184 is guided by a Bayesian optimal interval design and the RP2D will be determined on the basis of clinical safety, PK, and pharmacodynamic data. For patients with AML, disease assessment is performed according to modified European LeukemiaNet-International Working Group criteria. For patients with NSCLC, response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Treatment can continue until disease progression or intolerable toxicity. Biomarker assessments will include longitudinal profiling of peripheral blood immune cells and cytokines, analysis of HLA-A2 and survivin levels on AML bone marrow blasts and NSCLC tumor biopsies, and retrospective correlations of biomarker data with antitumor activity. Enrollment initiated in Sep 2020, with 7 patients enrolled as of Jan 2021. Clinical trial information: NCT04272203.