Artykuły w czasopismach: „Leeds melanoma Cohort”

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Newton-Bishop, Julia A., Samantha Beswick, Juliette Randerson-Moor, Yu-Mei Chang, Paul Affleck, Faye Elliott, May Chan i in. "Serum 25-Hydroxyvitamin D3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma". Journal of Clinical Oncology 27, nr 32 (10.11.2009): 5439–44. http://dx.doi.org/10.1200/jco.2009.22.1135.

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Purpose A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years). Results In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D3 levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D3 levels on RFS. Conclusion Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D3 levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.

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Newton Bishop, J. A., S. Beswick, J. Randerson-Moor, Y. Chang, P. Affleck, F. Elliott, D. Elder, J. Barrett i T. Bishop. "Serum vitamin D levels, VDR, and survival from melanoma". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 9016. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9016.

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9016 Background: Vitamin D has pleiotropic effects, which may moderate the interaction between patients and their tumors. Two studies were carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods: A pilot retrospective case-control study in 271 melanoma patients suggested that vitamin D may protect against recurrence of melanoma. We then tested these findings in a survival analysis in a cohort of 872 cases recruited to the Leeds Melanoma Cohort (median follow up of 4.7 years). Results: Pilot study Results suggested that taking vitamin D reduced the risk of relapse from melanoma (OR 0.6, 95% CI: 0.4, 1.1). Non-relapsers had higher mean 25-dihydroxyvitamin D3 levels than relapsers (49 nmol/L compared with 46, p=0.3). Cohort study Higher 25-dihydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis and were independently protective of relapse and death: hazard ratio (HR) for relapse free survival (RFS) 0.76, 95% CI: (0.64, 0.96), for a 20nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-dihydroxyvitamin D3 levels on RFS. Conclusions: The pilot study provided preliminary evidence for a role for vitamin D in outcome from melanoma. The cohort study provided further evidence that higher 25-dihydroxyvitamin D3 levels, at diagnosis, were associated both with thinner tumors and better survival, independent of Breslow thickness, from melanoma. Melanoma patients should avoid vitamin D deficiency. Further studies are needed to establish optimal serum levels for melanoma patients. No significant financial relationships to disclose.

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Newton‐Bishop, Julia A., John R. Davies, Faheem Latheef, Juliette Randerson‐Moor, May Chan, Jo Gascoyne, Saila Waseem, Susan Haynes, Charles O'Donovan i D. Timothy Bishop. "25‐Hydroxyvitamin D 2 /D 3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort". International Journal of Cancer 136, nr 12 (13.12.2014): 2890–99. http://dx.doi.org/10.1002/ijc.29334.

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Emran, Abdullah Al, Jérémie Nsengimana, Gaya Punnia-Moorthy, Ulf Schmitz, Stuart J. Gallagher, Julia Newton-Bishop, Jessamy C. Tiffen i Peter Hersey. "Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts". Cancers 12, nr 8 (28.07.2020): 2082. http://dx.doi.org/10.3390/cancers12082082.

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Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.

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Boon, Ian S., Peter Bownes, Shirin Namini, Carolyn Richardson i Satiavani Ramasamy. "Implementation of high dose rate (HDR) skin brachytherapy using the Valencia applicator: Leeds Cancer Centre non-melanoma cohort". Clinical Oncology 31 (październik 2019): e15. http://dx.doi.org/10.1016/j.clon.2019.09.042.

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Wang, Minyu, Soroor Zadeh, Angela Pizzolla, Kevin Thia, David E. Gyorki, Grant A. McArthur, Richard A. Scolyer i in. "Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation". Journal for ImmunoTherapy of Cancer 10, nr 4 (kwiecień 2022): e004095. http://dx.doi.org/10.1136/jitc-2021-004095.

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BackgroundPatients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy.MethodsIn this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC).ResultsIn single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural killer (NK) cells and NKT cells. We then validated this finding using bulk RNA-seq data from the skin cutaneous melanoma cohort in The Cancer Genome Atlas and deconvoluted the data using seven different algorithms. Interestingly, BRAF-mutant tumors had more CD4+ T cells than BRAF-wt samples in both primary and metastatic cohorts. In the metastatic cohort, BRAF-mutant melanoma demonstrated more B cells but less CD8+ T cell infiltration when compared with BRAF-wt samples. In addition, we further investigated the immune cell infiltrate using flow cytometry and multiplex IHC techniques. We confirmed that BRAF-mutant melanoma metastases were enriched for CD4+ T cells and B cells and had a co-existing decrease in CD8+ T cells. Furthermore, we then identified B cells were associated with a trend for improved survival (p=0.078) in the BRAF-mutant samples and Th2 cells were associated with prolonged survival in the BRAF-wt samples.ConclusionsIn conclusion, treatment-naive BRAF-mutant melanoma has a distinct immune context compared with BRAF-wt melanoma, with significantly decreased CD8+ T cells and increased B cells and CD4+ T cells in the tumor microenvironment. These findings indicate that further mechanistic studies are warranted to reveal how this difference in immune context leads to improved outcome to combination immune checkpoint blockade in BRAF-mutant melanoma.

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Hassel, Jessica Cecile, Heiko Smetak, Martin Salzmann, Matthias Haefner, Denise Bernhardt, Ingrid Hülsmeyer, Alexander Enk, Juergen Debus i Philipp Beckhove. "Evaluation of radiotherapeutic and immune-modulatory response to whole brain radiotherapy or stereotactic radiosurgery in patients with brain metastases from malignant melanoma treated with or without ipilimumab (ELEKTRA)." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e14104-e14104. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14104.

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e14104 Background: Immune checkpoint blockers have dramatically improved the survival of patients (pts) suffering from advanced metastasized melanoma. In pts with melanoma brain metastases (MBM) a combination with radiotherapy (RT) is routinely used. Methods: We prospectively included 106 pts with MBM in a non-randomized observational trial with 7 treatment cohorts. Patients in cohort 1-4 were treated with ipilimumab (+/- nivolumab) and either stereotactic (up to 3 MBM) or whole brain RT (≥ 4 MBM) before or after the start of immunotherapy. Cohort 5 and 6 included pts who received RT with an ipilimumab-free systemic treatment and cohort 7 pts were treated with ipilimumab (+/- nivolumab) and no RT. Primary endpoints were immunological response in the peripheral blood (FACS of T cell subsets, ELISpots against melanoma antigens) and radiological response, secondary endpoints were progression free and overall survival. Results: Included pts were in median 61 years old, 72% were male. At trial inclusion, 31% of pts had an elevated LDH. 39% of ipilimumab treated pts received combination therapy with nivolumab. Clinically, ipilimumab treated pts in the early RT groups had better responses of both intra- and extracranial disease (p = 0.04 for both). Multivariate analyses showed a better PFS for pts with early RT (p = 0.02) and normal LDH (p = 0.049). Type of radiation (p = 0.6) and immune therapy (p = 0.8) had no significant influence in this small cohort of pts. Immune monitoring revealed that ipilimumab leads to an increase in activated CD4+ and CD8+ T cells in the peripheral blood which was maintained in responding pts and higher in pts receiving early RT. Treg were not depleted in general but activated by ipilimumab. However, responders displayed a temporary decrease of Treg and activated Treg under treatment. An increase in the detection of melanoma antigens could be observed after 2 cycles of ipilimumab which was higher in pts with combined radioimmunotherapy compared to ipilimumab only. Conclusions: Preliminary data from this small observational trial might lead to a preference of a treatment sequence with radiotherapy first, followed by checkpoint inhibition in pts with MBM.

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Shah, Hemali, Paul Feustel i Lindy Davis. "Survivorship care plans and adherence with surveillance schedule in patients with invasive melanoma." Journal of Clinical Oncology 39, nr 15_suppl (20.05.2021): e24079-e24079. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e24079.

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e24079 Background: Melanoma accounts for 5.5% of new cancer diagnoses in the United States, and the 5-year overall survival is 93%. Overall, 7% of patients develop a recurrence, and 4-8% develop a second primary melanoma. This study aimed to assess how the standards set by the American College of Surgeons Commission on Cancer (CoC) to provide survivorship care plans (SCP) to patients may improve adherence to surveillance visits. Methods: All patients treated for invasive melanoma at our institution between 8/2018-2/2020 were included. SCP containing stage, treatment summary, and surveillance plan were delivered in-person to patients and sent to primary providers and dermatologists as outlined by CoC Standards for Optimal Care. Psychosocial distress (PSD) screening was performed using the National Comprehensive Cancer Network Distress Thermometer, with scores > 4 requiring further evaluation by oncology social worker. SCP and PSD were provided during the initiation phase of our cancer care program, and half the patients received services. Surveillance adherence was determined from chart review. The two groups were compared by t-test for continuous or chi-square test for categorical variables. Multiple regression analysis with odds ratios were performed. Mann-Whitney analysis was performed to assess the impact of SCP on PSD. Results: Of 146 patients identified for our cohort, 73 received SCP and PSD screening. Stage IA was the most common diagnosis (44%), followed by IB (13%) and IIIC (9%). Ninety-eight patients (67%) were adherent to all surveillance visits, and 55 of these received SCPs. Most patients noted low distress without the need for further support (79%), and 12 (21%) scored ≥4, benefiting from emotional and financial support and appointment and health insurance navigation. High PSD score did not correlate with advanced stage. Reception of SCP (p = 0.036) and close distance to treating facility (p = 0.016) improved adherence to surveillance visits. For patients who did not receive SCP, likelihood to follow up decreased by a factor of 0.469 (95% CI 0.231 - 0.952). Sex, age, PSD score, and stage did not affect surveillance adherence (p = NS). There were 6 recurrences, of which 4 were physician-detected during surveillance, and 8 patients developed second primary melanomas, all physician-detected. Conclusions: Delivery of SCP, a component of which includes counseling regarding signs and symptoms of recurrence or possibility of second primary melanoma, leads to significantly higher rates of surveillance adherence. This was shown for all stages. Melanoma survivors require close clinical follow-up, as demonstrated by our study finding that even with patient education, most recurrences and all new primary melanomas were physician-detected. PSD among melanoma patients is common, and all patients regardless of stage should undergo screening, as even early-stage patients exhibited distress.

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Meador, Lydia, Hari Menon, Haiyan Cui, Denise J. Roe, David J. DiCaudo i Karen Taraszka Hastings. "Inflammation induces GILT expression in human melanoma". Journal of Immunology 200, nr 1_Supplement (1.05.2018): 178.28. http://dx.doi.org/10.4049/jimmunol.200.supp.178.28.

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Abstract T cell-mediated immunity can produce durable anti-melanoma responses resulting in improved survival of metastatic melanoma patients. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens to CD4+ T cells and facilitates cross-presentation on MHC class I for activation of CD8+ T cells. Our prior study found that GILT expression is increased in melanocytes of malignant melanoma specimens compared with benign nevi. To determine whether GILT expression is associated with inflammation, expression in halo nevi specimens was compared to nevi without lymphocytic infiltrate by immunohistochemistry. A halo nevus is a benign nevus with a lymphocytic infiltrate which leads to regression of the nevus. GILT, but not MHC class II, expression was increased in melanocytes of halo nevi compared to nevi without lymphocytic infiltrate. Analysis of a publicly available gene expression profiling cohort of 457 cutaneous melanoma specimens revealed that GILT expression was associated with IFN-γ, TNF-α, and IL-1β expression in human melanoma. In vitro exposure of human melanoma cell lines to IFN-γ or inflammatory cytokines, such as TNF-α, induced GILT expression in melanoma cell lines, which lacked GILT expression at baseline. Vemurafenib, a BRAF inhibitor used in the treatment of metastatic melanoma, enhanced IFN-γ-induced GILT and MHC class II expression in a melanoma cell line. Together these data demonstrate that inflammation, alone or in combination with a current therapeutic agent, induces high levels of GILT expression in human melanoma.

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Brendlin, Andreas Stefan, Felix Peisen, Haidara Almansour, Saif Afat, Thomas Eigentler, Teresa Amaral, Sebastian Faby, Adria Font Calvarons, Konstantin Nikolaou i Ahmed E. Othman. "A Machine learning model trained on dual-energy CT radiomics significantly improves immunotherapy response prediction for patients with stage IV melanoma". Journal for ImmunoTherapy of Cancer 9, nr 11 (listopad 2021): e003261. http://dx.doi.org/10.1136/jitc-2021-003261.

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BackgroundTo assess the additive value of dual-energy CT (DECT) over single-energy CT (SECT) to radiomics-based response prediction in patients with metastatic melanoma preceding immunotherapy.Material and methodsA total of 140 consecutive patients with melanoma (58 female, 63±16 years) for whom baseline DECT tumor load assessment revealed stage IV and who were subsequently treated with immunotherapy were included. Best response was determined using the clinical reports (81 responders: 27 complete response, 45 partial response, 9 stable disease). Individual lesion response was classified manually analogous to RECIST 1.1 through 1291 follow-up examinations on a total of 776 lesions (6.7±7.2 per patient). The patients were sorted chronologically into a study and a validation cohort (each n=70). The baseline DECT was examined using specialized tumor segmentation prototype software, and radiomic features were analyzed for response predictors. Significant features were selected using univariate statistics with Bonferroni correction and multiple logistic regression. The area under the receiver operating characteristic curve of the best subset was computed (AUROC). For each combination (SECT/DECT and patient response/lesion response), an individual random forest classifier with 10-fold internal cross-validation was trained on the study cohort and tested on the validation cohort to confirm the predictive performance.ResultsWe performed manual RECIST 1.1 response analysis on a total of 6533 lesions. Multivariate statistics selected significant features for patient response in SECT (min. brightness, R²=0.112, padj. ≤0.001) and DECT (textural coarseness, R²=0.121, padj. ≤0.001), as well as lesion response in SECT (mean absolute voxel intensity deviation, R²=0.115, padj. ≤0.001) and DECT (iodine uptake metrics, R²≥0.12, padj. ≤0.001). Applying the machine learning models to the validation cohort confirmed the additive predictive power of DECT (patient response AUROC SECT=0.5, DECT=0.75; lesion response AUROC SECT=0.61, DECT=0.85; p<0.001).ConclusionThe new method of DECT-specific radiomic analysis provides a significant additive value over SECT radiomics approaches for response prediction in patients with metastatic melanoma preceding immunotherapy, especially on a lesion-based level. As mixed tumor response is not uncommon in metastatic melanoma, this lends a powerful tool for clinical decision-making and may potentially be an essential step toward individualized medicine.

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Amaro, Adriana, Michela Croce, Silvano Ferrini, Gaia Barisione, Marina Gualco, Patrizia Perri, Ulrich Pfeffer i in. "Potential Onco-Suppressive Role of miR122 and miR144 in Uveal Melanoma through ADAM10 and C-Met Inhibition". Cancers 12, nr 6 (4.06.2020): 1468. http://dx.doi.org/10.3390/cancers12061468.

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Uveal melanoma (UM) is a rare tumor of the eye that leads to deadly metastases in about half of the patients. ADAM10 correlates with c-Met expression in UM and high levels of both molecules are related to the development of metastases. MiR122 and miR144 modulate ADAM10 and c-Met expression in different settings. We hypothesized a potential onco-suppressive role for miR122 and miR144 through modulation of ADAM10 and c-Met in UM. We analyzed the UM Cancer Genome Atlas data portal (TCGA) dataset, two other cohorts of primary tumors and five human UM cell lines for miR122 and miR144 expression by miR microarray, RT-qPCR, Western blotting, miR transfection and luciferase reporter assay. Our results indicate that miR122 and miR144 are expressed at low levels in the UM cell lines and in the TCGA UM dataset and were down-modulated in a cohort of seven UM samples, compared to normal choroid. Both miR122 and miR144 directly targeted ADAM10 and c-Met. Overexpression of miR122 and miR144 led to reduced expression of ADAM10 and c-Met in the UM cell lines and impaired cell proliferation, migration, cell cycle and shedding of c-Met ecto-domain. Our results show that miR122 and miR144 display an onco-suppressive role in UM through ADAM10 and c-Met modulation.

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Narous, M., Z. Nugent, H. Singh i C. N. Bernstein. "A164 RISKS OF SKIN CANCERS PRE- AND POST-INFLAMMATORY BOWEL DISEASE DIAGNOSIS". Journal of the Canadian Association of Gastroenterology 5, Supplement_1 (21.02.2022): 42–43. http://dx.doi.org/10.1093/jcag/gwab049.163.

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Abstract Background Inflammatory bowel disease (IBD) has been shown to be associated with an increased risk of non-melanoma skin cancers (NMSC), specifically squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), with the use of immunosuppressants such as thiopurines and tumor necrosis factor inhibitors (anti-TNFa). However, there is no literature exploring risk of skin cancers prior to formal Crohn’s disease (CD) or ulcerative colitis (UC) diagnoses. An increased risk pre IBD diagnosis could potentially suggest varied immunological impairments in patients with IBD. Aims To compare risks of NMSC and melanoma preceding and following a diagnosis of IBD and to evaluate the effect of thiopurines and anti-TNFa on risk of skin cancers in IBD. Methods This is a retrospective, historical cohort study using population-based data sources including the University of Manitoba IBD Epidemiology Database and the Manitoba Cancer Registry. Individuals with IBD diagnosed between 1987 and 2018 (N = 9344 / 636 NMSC) were identified and matched with randomly selected controls (N = 88916 / 3839 NMSC) based on age, sex, and postal area of residence on the date of IBD diagnosis (index date). Logistic and Cox regression analyses were performed to calculate adjusted risks skin cancers prior to and after IBD diagnosis. Results Subjects with IBD were more likely to have BCC pre-dating their IBD diagnosis (OR 1.50, 95% CI 1.24–1.81). Risks of SCC, other non-melanoma skin cancers, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risk of BCC and SCC were significantly increased across all IBD groups (HR 1.60, 95% CI 1.45–1.76 and HR 1.65, 95% CI 1.37–1.99), except for SCC in UC. There was no significant association between melanoma and IBD post-IBD diagnosis. Thiopurines are associated with higher risks of BCC, SCC, and melanoma in IBD. Anti-TNFa use also raised risks of BCC and melanoma, but anti-TNFa alone did not increase risk of SCC in IBD. Nested case-control analysis confirmed a higher baseline risk of BCC in patient with IBD with censoring of both thiopurines and anti-TNFa. Similarly, censoring of both medications produced no effect on risk of SCC in IBD corroborating the absence of a baseline SCC risk in IBD. Conclusions The risk of BCC preceding a formal diagnosis of IBD is higher than in non-IBD controls, compared to a generally increased risk of NMSC post-IBD diagnosis. IBD is not associated with a significant risk of melanoma, although risk for melanoma is increased with thiopurine or anti-TNFa exposure. Our study suggests a possible inherent immune impairment in patients with IBD that leads to BCC. Thiopurine and anti-TNF therapy increase the risks for skin cancers evident in persons with IBD after their diagnoses. Funding Agencies None

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Kuan, Feng-Che, Chung-Sheng Shi i Meng-Hung Lin. "Correlation of BRAF genomic alterations with higher mutation burden and predictive response to immune checkpoint inhibitors among human malignancies." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): e14589-e14589. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e14589.

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e14589 Background: The treatment of BRAF-mutated melanoma leads the evolution of management in BRAF-mutated human malignancies from targeted agents to immune checkpoint inhibition. The correlation between BRAF genomic alterations and mutation burden is not well-studied as well as its prognostic role and predictive role to immune checkpoint inhibitors. Methods: Three Public genomic database (AACR GENIE v.11 [N = 119,058], MSKCC pan-cancer [10,080], MSKCC ICI [1,608]) were retrieved from cBioPortal ( https://www.cbioportal.org ). Raw data of cancer types, BRAF status, mutation counts (MC), exposure to immune checkpoints inhibitors (ICIs), and survival were analyzed. Violin plots were used to compare the distribution of MC among BRAF-altered and -wild tumors, and the Kaplan-Meier method was used to estimate survival rates. Statistical significance was set at a two-sided P < 0.05. Results: BRAF genomic alterations exist in 7,361 (6.2%, AACR GENIE v.11), 560 (5.6%, MSKCC pan-cancer) and 165 patients (10.3%, MSKCC ICI). There are 4,851 (4.1%), 357 (3.6%), and 312 (19.4%) patients with melanoma in these database, respectively. AACR GENIE v.11 includes the other two MSKCC databases, and 10.7% (N = 1,074) patients in MSKCC pan-cancer databases are also cases in MSKCC ICI. The median MCs were 7/Mb and 4/Mb, with interquartile ranges of 1 to 1,467 and 1 to 821 in the BRAF-altered and -wild tumors in AACR GENIE v.11. In this three databases, the distribution of MC was different between the BRAF-altered and -wild tumors (p < 0.001). In MSKCC pan-cancer cohort, the median overall survival in BRAF-altered and -wild tumors are 22.8 vs. 26.3 months (logrank p = 0.005). In MSKCC ICI cohort, the median overall survival of BRAF-altered and -wild tumors are 47.0 vs. 17.0 months (logrank p < 0.001). Conclusions: BRAF genomic alterations are associated with higher mutation counts, represent a poor prognostic factor and positively predictive to immune checkpoint inhibition among human malignancies.

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Kuan, Feng-Che, Chung-Sheng Shi i Meng-Hung Lin. "Correlation of BRAF genomic alterations with higher mutation burden and predictive response to immune checkpoint inhibitors among human malignancies." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): e14589-e14589. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e14589.

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e14589 Background: The treatment of BRAF-mutated melanoma leads the evolution of management in BRAF-mutated human malignancies from targeted agents to immune checkpoint inhibition. The correlation between BRAF genomic alterations and mutation burden is not well-studied as well as its prognostic role and predictive role to immune checkpoint inhibitors. Methods: Three Public genomic database (AACR GENIE v.11 [N = 119,058], MSKCC pan-cancer [10,080], MSKCC ICI [1,608]) were retrieved from cBioPortal ( https://www.cbioportal.org ). Raw data of cancer types, BRAF status, mutation counts (MC), exposure to immune checkpoints inhibitors (ICIs), and survival were analyzed. Violin plots were used to compare the distribution of MC among BRAF-altered and -wild tumors, and the Kaplan-Meier method was used to estimate survival rates. Statistical significance was set at a two-sided P < 0.05. Results: BRAF genomic alterations exist in 7,361 (6.2%, AACR GENIE v.11), 560 (5.6%, MSKCC pan-cancer) and 165 patients (10.3%, MSKCC ICI). There are 4,851 (4.1%), 357 (3.6%), and 312 (19.4%) patients with melanoma in these database, respectively. AACR GENIE v.11 includes the other two MSKCC databases, and 10.7% (N = 1,074) patients in MSKCC pan-cancer databases are also cases in MSKCC ICI. The median MCs were 7/Mb and 4/Mb, with interquartile ranges of 1 to 1,467 and 1 to 821 in the BRAF-altered and -wild tumors in AACR GENIE v.11. In this three databases, the distribution of MC was different between the BRAF-altered and -wild tumors (p < 0.001). In MSKCC pan-cancer cohort, the median overall survival in BRAF-altered and -wild tumors are 22.8 vs. 26.3 months (logrank p = 0.005). In MSKCC ICI cohort, the median overall survival of BRAF-altered and -wild tumors are 47.0 vs. 17.0 months (logrank p < 0.001). Conclusions: BRAF genomic alterations are associated with higher mutation counts, represent a poor prognostic factor and positively predictive to immune checkpoint inhibition among human malignancies.

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Champiat, Stephane, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey i in. "Abstract CT188: ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial". Cancer Research 82, nr 12_Supplement (15.06.2022): CT188. http://dx.doi.org/10.1158/1538-7445.am2022-ct188.

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Abstract Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [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 CT188.

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George, Thomas J., Ji-Hyun Lee, Peter Joel Hosein, David L. DeRemer, Jonathan Alexander Chatzkel, Brian Hemendra Ramnaraign, Sherise C. Rogers i in. "Results of a phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response pathway deficient neoplasms." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 3122. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3122.

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3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.

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George, Thomas J., Ji-Hyun Lee, Peter Joel Hosein, David L. DeRemer, Jonathan Alexander Chatzkel, Brian Hemendra Ramnaraign, Sherise C. Rogers i in. "Results of a phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response pathway deficient neoplasms." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 3122. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3122.

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3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.

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Beasley, Georgia, Nellie Farrow, Karenia Landa, Maria Angelica Seilm, Sin-Ho Jung, Darell Bigner, Andrea True Kelly, Smita Nair, Matthias Gromeier i April Salama. "302 A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (listopad 2020): A329. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0302.

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BackgroundWhile PD-1/PD-L1 antagonists have improved the prognosis for many patients with melanoma, the majority fail therapy. PVSRIPO is a novel immunotherapy consisting of a non-neurovirulent rhinovirus:poliovirus chimera that activates innate immunity to facilitate a targeted anti-tumor immune response. Preclinical data show that PVSRIPO plus anti-PD-1 therapy leads to a greater anti-tumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (AJCC version 7 stage IIIB, IIIC, or IV) was performed. Eligible patients failed at least prior anti-PD-1 and BRAF/MEK (if BRAF mutant) therapy. The primary objective was to characterize the safety and tolerability of PVSRIPO. 12 patients in 4 cohorts received a total of 1, 2 (into 2 different lesions) or 3 (same lesion 3x or 3 different lesions) injections of PVSRIPO monotherapy, 21 days apart.ResultsPVSRIPO injections were well tolerated with no SAEs or DLTs reported; all TEAEs were grade (G) 1 or 2 (grade 1 pruritus most common at 58%), with all but 2 PVSRIPO-related TEAEs localized to the injected or adjacent lesions ( n=1 G1 hot flash, n=1 G1 fatigue). Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients >5 lesions), 4 of 12 patients (33%) achieved an objective response per irRC, including 4/6 (66%) who received 3 injections (maximum administered). Pathologic complete response (ie, no viable tumor detected in injected and non-injected lesions biopsied) was observed in 2 of 4 (50%) patients with in-transit disease. PVSRIPO response relative to time since prior anti-PD-1 exposure is summarized in table 1. Following study completion/PVSRIPO therapy, 10/12 patients (83%) again received immune checkpoint inhibitor (ICI)-based therapy and 6/12 patients (50%) remained progression free at the data cutoff.Abstract 302 Table 1PVSRIPO anti-tumor response relative to ICI administration and post-study disease statusConclusionsIntratumoral PVSRIPO was well tolerated. When taken together with preclinical data, the anti-tumor responses observed relative to prior or subsequent ICI therapy suggests that PVSRIPO, either alone or in combination with anti-PD-1, may be an effective treatment in anti-PD-1 refractory melanoma. An amendment exploring higher PVSRIPO dose levels is ongoing and a phase 2 study with and without anti-PD-1 in the refractory population is initiating.Ethics ApprovalThis study (NCT03712358) was approved by WIRB; ID 20181772.

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Park, Jong Chul, Hatem Soliman, Gerald Falchook, Taofeek Owonikoko, Anna Spreafico, Erminia Massarelli, Meredith McKean i in. "511 Initial results of a phase 1 study of intratumoral ONCR-177, an oncolytic herpes-simplex virus-1 expressing five immunomodulatory transgenes, in subjects with advanced injectable tumors". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (listopad 2021): A542. http://dx.doi.org/10.1136/jitc-2021-sitc2021.511.

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BackgroundONCR-177 is a recombinant oncolytic herpes simplex virus (oHSV) that retains γ34.5 and is engineered to express five immunomodulatory transgenes (IL-12, FLT3LG ECD, CCL4 and anti-PD-1 and anti-CTLA-4 antibodies) for the intratumoral treatment of solid tumors. Attenuation by miRNA leads to selective replication in tumor cells, and mutations in UL37 act as an orthogonal safety strategy. Transgenes elicit potent systemic stimulation of anti-tumor immunity.1 ONCR-177 is being tested in an open-label, multicenter, phase 1 study alone and in combination with pembrolizumab (NCT04348916), for surface lesion injection and intrahepatic injection. Here we present the surface lesion escalation data.MethodsThe objectives were determination of safety and recommended phase 2 dose (RP2D) of ONCR-177 monotherapy in subjects with advanced and/or refractory injectable surface lesions using a modified toxicity probability interval-2 (mTPI-2) escalation design at four dose levels: (Cohort 1: 1×106 PFU in 1 mL, Cohort 2: 1×107 PFU in 1 mL, Cohort 3: 1×108 PFU in 1 mL and Cohort 4: 4×108 PFU in 4 mL). Subjects received ONCR-177 by intratumoral injection once every 2 weeks (up to 10 times) until disease progression or unacceptable toxicity. There was no intrapatient dose escalation.ResultsAs of June 28, 2021, 14 subjects with injectable tumors were enrolled in the dose escalation phase (3 in cohort 1, 4 in cohort 2, 3 in cohort 3 and 4 in cohort 4). Enrolled tumor types included: melanoma (3), breast (3), anal squamous cell (1), lung (1), duodenal (1), basal cell (1), chondrosarcoma (1), thyroid (1), oropharyngeal (1) and papillary renal cell (1). Subject median age was 67 years. Median number of prior lines of therapy was 4 (range 2–11), including 11 of 14 subjects with prior immunotherapy. Nine subjects were HSV-1 seropositive at baseline, 4 were negative, one was unknown. Treatment-related Adverse Events were all Grade 1–2. Most commonly reported were: cytokine release syndrome (2 occurrences in Cohort 4), fatigue, nausea, chills, headache, decreased appetite, hypotension, and injection site pain. There were no dose-limiting toxicities. The RP2D was selected as 4×108 PFU in 4 mL every 2 weeks up to 10 doses. Clinical data, including safety, viral shedding and exploratory biomarker data including peripheral payloads, peripheral cytokines and immune infiltration and PD-L1 expression in the tumor microenvironment will be presented.ConclusionsONCR-177 monotherapy in heavily pretreated subjects with advanced, injectable, solid tumors at the RP2D was safe and tolerable. Enrollment at the RP2D is underway in monotherapy expansion.Trial RegistrationNCT04348916ReferencesHaines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, Wambua D, Kong L, Behera P, Jacques J, et al. ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity. Cancer Immunol Res 2021;9: 291–308Ethics ApprovalThis study was approved by the following institutional Ethics Boards:-University Health Network Research Ethics Board (ID Number: 20-5069)-Integreview IRB (ID Number RM 694) -WCG IRB (ID Number: 20200150)-Advarra (ID Number: 00000971)-Roswell Park IRB (ID Number: STUDY00001189/P-553719)-The Ohio State University Cancer IRB (ID Number: 2020C0139) -Dana Farber Cancer Institute IRB (ID Number 354020)All participants gave informed consent before taking part in this clinical trial.

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Beasley, Georgia M., Smita K. Nair, Norma E. Farrow, Karenia Landa, Maria Angelica Selim, Carol Ann Wiggs, Sin-Ho Jung i in. "Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma". Journal for ImmunoTherapy of Cancer 9, nr 4 (kwiecień 2021): e002203. http://dx.doi.org/10.1136/jitc-2020-002203.

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BackgroundWhile programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.ResultsPVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.ConclusionIntratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.Trial registration numberNCT03712358

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Owonikoko, Taofeek K., Justin C. Moser, Janet Yoon, Emily K. Slotkin, Afshin Dowlati, Vincent T. Ma, Maria Düring i Joen Sveistrup. "Phase 1 trial of GD2-SADA:¹⁷⁷Lu-DOTA drug complex in patients with recurrent or refractory metastatic solid tumors known to express GD2 including small cell lung cancer (SCLC), sarcoma, and malignant melanoma." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): TPS3162. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.tps3162.

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TPS3162 Background: GD2 is a disialoganglioside with high expression in small cell lung cancers (SCLC), sarcomas and melanomas and limited expression in normal tissues. The SADA platform represents a 2-step pretargeted radioimmunotherapy approach developed to optimize tumor targeting and reduce normal tissue irradiation. The GD2-SADA molecule is composed of a non-radioactive, bispecific antibody (anti-GD2 x anti-DOTA) linked to a tetramerization sequence from the p53 protein. In the first step, the GD2-SADA molecule is administered in a tetrameric form with a high affinity to the GD2 tumor target. In preclinical research, any unbound GD2-SADA molecule will disassemble to monomers and has shown to clear via the kidneys. In the second step, the radioactive payload 177Lu-DOTA is administered, which binds to the anti-DOTA part of the GD2-SADA and leads to radiation-induced damage at the target and has shown limited exposure to non-target tissues in preclinical research. This pre-targeting approach supports the concept of highly focused irradiation of the tumor target with the potential of administering higher radioactivity doses. Methods: Trial 1001 (NCT05130255) is a first-in-human, dose-escalation, single-arm, open-label, non-randomized, multicenter phase 1 trial with the purpose of evaluating safety and tolerability of GD2-SADA:177Lu-DOTA. The trial is composed of 3 parts: Part A is dose escalation of the GD2-SADA dose and testing of different intervals between GD2-SADA and 177Lu-DOTA. Part B is dose escalation of the 177Lu-DOTA radioactivity dose to establish its maximum tolerated dose (MTD). Part C involves repeated dosing to assess the safety profile and determine the Recommended Phase 2 Dose (RP2D). Parts B and C may only begin upon completion of dose-limiting toxicity (DLT) observation period of Parts A and B, respectively. Escalation is based on classical 3+3 design. Parts A, B, and C will include 18, 12, and 32 patients, respectively. Patients can only be assigned to one part of the trial. The trial will include adult/adolescent patients with either SCLC, sarcoma, or melanoma with radiographical relapse/progression on standard therapies. The patients must be in ECOG performance status 0-1 and have adequate hematological, renal, and liver function. The patients must have measurable disease according to RECIST 1.1. Patients with active CNS metastases are ineligible. Safety endpoints (DLTs and adverse events) will be summarized by trial part and cohort. Objective response according to RECIST 1.1 and disease control rates at 6, 12 and 24 months will be presented with exact 95% CI. PFS, OS, and duration of response will be estimated using Kaplan-Meier methods. Additional objectives include dosimetry, PK, and immunogenicity data. The study is actively enrolling at US sites. Clinical trial information: NCT05130255 .

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Ricart, A. D., M. Cooney, J. Sarantopoulos, J. Brell, K. W. Locke, R. E. Gammans, G. Medina, A. Zambito, A. W. Tolcher i S. C. Remick. "A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 3096. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3096.

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3096 Background: MN-029 is a novel VDA that binds reversibly to the colchicine-binding site on tubulin and inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor endothelial cells (EC). Disruption of the tumor EC cytoskeleton ultimately leads to a temporary reduction in tumor blood flow. Methods: MN-029 is administered IV as a 10–20 min infusion, at 3-wk intervals in pts with advanced cancer. The study has followed an accelerated titration design, with intrapatient dose escalation. PD effects on tumor blood flow are evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 28 pts were enrolled (13M/15F), median age 56 (range 35 - 76) and tumor types: colorectal (5), renal (5), hepatocellular (3), ovarian (2), melanoma (2), soft tissue sarcoma (2), carcinoid (2) and others (7). A total of 110 cycles of MN-029 were given, median 3/pt (range 1–20), over 9 dose levels (4, 8, 16, 24, 36, 54, 80, 120 and 180 mg/m2). Escalation proceeded until an initial dose-limiting toxicity (DLT) was observed in 1 pt in the 180 mg/m2 cohort, consisting of a reversible episode (3 hours post dose) of acute coronary ischemia (without sequelae and with preservation of myocardial function) probably due to coronary vasospasm. Therefore, this cohort was expanded to 6 pts, with no further DLTs observed. Common mild to moderate toxicities included nausea, vomiting (which appears dose-related), hypotension, fatigue and diarrhea. There was no significant myelotoxicity, stomatitis or alopecia. Seven pts had stable disease after 3 cycles, including 2 pts with carcinoid tumor (+21 cycles and +17 cycles). PK data generally indicated dose-related increases in Cmax and AUC values, although substantial inter-patient variability was observed. Tumor blood flow reduction assessed by DCE-MRI was recorded at 120 and 180 mg/m2, but not at 80 mg/m2. Conclusions: MN-029 produced reductions in tumor blood flow at doses that were well tolerated. Accrual continues at 225 mg/m2. [Supported in part by grants from MediciNova, Inc. and M01 RR-000080] [Table: see text]

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Pollack, Megan, Allison Shayna Betof, Katherine Rappazzo, Ian Valentine, Zeynep Eroglu, Douglas Buckner Johnson i Alexander Noor Shoushtari. "Safety of resuming anti-PD-1 (aPD1) in patients (pts) with immune-related adverse events (irAEs) during combined anti-CTLA-4 (aCTLA4) and aPD1 in metastatic melanoma (MM)." Journal of Clinical Oncology 35, nr 15_suppl (20.05.2017): 9544. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9544.

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9544 Background: Combination aPD1 and aCTLA4 has demonstrated greater response rates (RR) than aPD1 alone in MM. However, aPD1 + aCTLA4 also leads to more frequent and severe irAEs compared to aPD1. The safety of resuming aPD1 following these irAEs is not known. We characterized the safety and efficacy of resuming aPD1 following severe irAEs during aPD1 + aCTLA4 in pts with MM. Methods: We retrospectively reviewed mm pts from 3 academic centers who had a severe irAE with aPD1 + aCTLA4 (defined as CTCAE v4.03 G3-4 or leading to early discontinuation of aPD1 + aCTLA4) and who resumed aPD1 thereafter. We assessed for frequency, timing, and spectrum of irAEs as well as RR, progression free survival (PFS) and overall survival (OS). Results: We identified 64 pts who received aPD1 + aCTLA4 for a median of 2 doses (range, 1-4). The most frequent irAEs that led to aPD1 + aCTLA4 discontinuation were: colitis (36%), hepatitis (23%), hypophysitis (8%), pneumonitis (5%), nephritis (3%), neurologic complications (3%), and pancreatitis (3%); eight pts (13%) had > 1 concurrent severe irAEs. aPD1 was resumed at a median of 55 days after last dose of aCTLA4 + aPD1 (range, 17-289); 23% experienced recurrence of the same irAE with aPD1 monotherapy, 16% experienced a distinct irAE, and 60% did not experience any severe irAE after resuming aPD1. Hepatitis recurred in 6 of 18 pts, pancreatitis in 2 of 2, dermatitis in 1 of 4, nephritis in 1 of 2, pneumonitis in 1 of 3, hypophysitis in 1 of 5, and colitis in 1 of 27; the grade of these recurrent irAEs was: 46% grade 1-2, 33% grade 3, 13% grade 4, and 7% grade 5 (n = 1). One death from irAEs occurred related to Toxic Epidermal Necrolysis (TEN). No difference was observed in time prior to resuming aPD1 in those that had recurrent irAEs vs. those without (median 56 days each). The RR in this cohort was 73% (30% CR; 44% PR); median PFS (range, 2.2-not reached (NR)) and OS (range, 2.4-NR) were not reached. Conclusions: In our experience, pts who resume aPD1 following irAEs with aPD1 + aCTLA4 exhibit variable toxicity profiles with most experiencing no irAEs, but a minority experiencing severe or life-threatening irAEs. We observed excellent efficacy in this cohort.

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Portuguese, Andrew J., Scott S. Tykodi, Christopher D. Blosser, Ted A. Gooley, John A. Thompson i Evan T. Hall. "Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review". Journal of the National Comprehensive Cancer Network 20, nr 4 (kwiecień 2022): 406–16. http://dx.doi.org/10.6004/jnccn.2022.7009.

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Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.

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Greif, Philipp A., Sebastian H. Eck, Nikola Konstandin, Anna Benet-Pages, Annika Dufour, Anna Vetter, Henning Popp i in. "Identification of Recurring Tumor-Specific Somatic Mutations In Acute Myeloid Leukemia by Transcriptome Sequencing." Blood 116, nr 21 (19.11.2010): 1059. http://dx.doi.org/10.1182/blood.v116.21.1059.1059.

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Abstract Abstract 1059 Aims: Genetic lesions are crucial for cancer initiation. Recently, whole genome sequencing using next generation technology was used as a systematic approach to identify mutations in genomes of various types of tumors including melanoma, lung and breast cancer as well as cytognetically normal acute myeloid leukaemia (CN-AML). Despite its technical feasibility, whole genome sequencing is still time consuming and cost intensive. As an alternative approach, here we identify tumor-specific somatic mutations by sequencing transcriptionally active genes. Methods: Mutations were detected by comparing the transcriptome sequence of a CN-AML with the corresponding remission sample. In a single Genome Analyzer II run, we generated 4.35 Gbp of CN-AML and 5.54 of remission transcriptome sequence from the same patient. 63% of AML reads and 74% of remission reads mapped to exon regions. 10,152 genes had an average read depth of at least 7-fold and 6,989 genes an average read depth of 20 or greater in both samples. By comparing the 8,978 coding Single Nucleotide Variants (SNVs) discovered in the CN-AML sample with the remission sample, we identified 5 non-synonymous mutations specific to the tumor sample. Results: We found 5 tumor-specific somatic mutations. Among them is a nonsense mutation affecting the RUNX1 gene, which is a frequent mutational target in AML, and a missense mutation in the putative tumor suppressor gene TLE4, which encodes a RUNX1 interacting protein. A second missense mutation was identified in SHKBP1, which acts downstream of FLT3, a receptor tyrosine kinase mutated in about 30% of AML cases. The frequency of mutations in TLE4 and SHKBP1 in a cohort of 95 CN-AML patients was 2%. Conclusion: Our study demonstrates that whole transcriptome sequencing leads to the rapid detection of recurring point mutations in the coding regions of genes relevant to malignant transformation. Disclosures: No relevant conflicts of interest to declare.

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Bothwell, Mia, Aaron Cheng, Leyre Zubiri, Meghan Mooradian, Yevgeniy R. Semenov, Gayle C. Blouin, Erica Tavares i in. "Patients with steroid-refractory toxicity following immune checkpoint inhibitors: Frequent hospitalizations and long duration of illness." Journal of Clinical Oncology 39, nr 15_suppl (20.05.2021): 2655. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2655.

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2655 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer with significantly improved outcomes, but these agents have a unique spectrum of toxicities known as immune-related adverse events (irAEs). The recommended treatment for non-endocrine toxicities is steroid based. However, a subset of patients (pts) is steroid-refractory and requires second-line immunosuppression. There is very little evidence regarding this population. In this retrospective study we report the 1) incidence 2) type of treatment used 3) natural history and 4) potential predictors of steroid-refractory irAE at a major academic medical center. Methods: The Research Patient Database Registry at Mass General Brigham was used to identify pts treated with an ICI from 1/5/2017 to 6/1/2019. Pharmaceutical records identified a subset of the cohort received a second-line immunosuppressive agent within a 15-month period after ICI. For pts with steroid-refractory irAE additional information was collected: demographics, ICI regimen, type/#/and severity of irAE, clinical characteristics, # of admissions, length of stay (LOS), amount and duration of steroid therapy, second line immunosuppression type, treatment discontinuation rates, response, and outcome of re-challenge. Multivariate logistic regressions were used to predict risk of refractory toxicity and study the association of different variables (age, sex, race, marital status, cancer and ICI types) with refractory toxicities. Results: We identified 61 pts (1.4%) with steroid-refractory irAEs (48 colitis, 4 myocarditis, 6 pneumonitis, 3 neurologic) out of the total ICI cohort (N=4,325). 60.7% received ICI monotherapy. 24.6% received ICI in the adjuvant setting. Median length of steroid duration was 68 days with max of 1135 days. Despite use of second line immunosuppression, 25.8% of pts were never able to discontinue steroids. Majority of pts (72.1%) had at least one hospitalization with median LOS of 7.5 days. 93.4% of pts permanently discontinued the ICI responsible for the irAE. Thirteen pts (21.3%) were later re-challenged with ICI and 7 (53.8%) of these developed a subsequent irAE. Anti-CTLA-4 therapy was associated with a 10-fold risk of refractory toxicity compared to PD-1 (p<.05). Best tumor response was complete response in 21.3% and partial response in 26.2%. Among different cancer types, melanoma was most strongly associated with refractory events (OR 2.97 in comparison to thoracic malignancy). Conclusions: Refractory toxicity is uncommon but leads to high rates of ICI discontinuation, frequent hospitalizations, and a long duration of illness with exposure to prolonged and high-doses of steroids. There is an urgent need for further investigation into predictive factors for steroid-refractory toxicity given that ICI is being used more frequently and in earlier lines of treatment.

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Bodei, Lisa, Petr Kavan, Moishe Liberman, Neil Taunk, Ur Metser, Daniel Juneau, Eileen Mary O'Reilly, Junsheng Ma, Richard Cioci i Albiruni Ryan Abdul Razak. "FRONTIER: FAPi radioligand open-label, phase 1 study to evaluate safety, tolerability and dosimetry of [Lu-177]-PNT6555—A dose escalation study for treatment of patients with select solid tumors." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): TPS3161. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.tps3161.

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TPS3161 Background: Fibroblast activation protein alpha (FAP) is a 170 kDa transmembrane glycoprotein expressed during development, active tissue remodeling, and cancer. Overexpression on cancer-associated fibroblasts in the tumor microenvironment, and on some cancer cells of mesenchymal origin, leads to the presence of FAP in > 90% of epithelial tumors, making FAP a compelling anti-cancer target. PNT6555, a potent FAP-targeting compound with rapid clearance from normal tissues and prolonged tumor retention in preclinical models1, is a radioligand consisting of a DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) and a FAP-targeting moiety (Bz-D-Ala-boroPro) connected via an aminomethyl linker. The corresponding gallium-68 and lutetium-177 chelates constitute the imaging and therapeutic theranostic pair of PNT6555 under evaluation in this phase I study. Methods: FRONTIER (NCT05432193) is a multicenter, open-label, multi-dose phase I study of PNT6555 in participants with pancreatic ductal adenocarcinoma, esophageal cancer, colorectal cancer, melanoma skin cancer, cholangiocarcinoma, or soft tissue sarcoma solid tumors with FAP over-expression. The primary aim is to evaluate the safety and tolerability of [Lu-177]-PNT6555 in order to determine a recommended phase II dose (RP2D). Dosimetry, pharmacokinetics, and tumor and immune responses will also be assessed for [Lu-177]-PNT6555, as well as safety, tolerability, and diagnostic performance of [Ga-68]-PNT6555 PET/CT. Key eligibility criteria include being refractory to prior treatment with no alternative available therapeutic options, having adequate organ function, and being FAP-positive on [Ga-68]-PNT6555 PET/CT scan, defined as ≥50% of lesions with an SUVmax of ≥1.5x the liver SUVmean. [Ga-68]-PNT6555 will be dosed at 120 - 220 MBq (3.2 - 5.9 mCi), with PET/CT initiated 90 (±30) min later. FAP-positive participants will receive [Lu-177]-PNT6555 once every 6 weeks for up to 6 cycles. Starting at 4 GBq (108 mCi) ±10%, [Lu-177]-PNT6555 may be escalated by 4 GBq, with a maximum planned dose of 12 GBq. De-escalation by 2 GBq may also occur. Dose finding will be guided by the modified toxicity probability interval (mTPI-2) statistical design with a targeted toxicity rate of 30%. The planned total sample size is 30, with targets of 3-12 DLT evaluable patients per dose level. Cohort 1 has been completed without a DLT. Enrollment to cohort 2 began in January 2023. 1. Hallet R, et al. Pre-clinical characterization of the novel fibroblast activation protein (FAP) targeting ligand PNT6555 for the imaging and therapy of cancer. Presented at SNMMI Annual Meeting April 2022; Vancouver, BC, Canada. Clinical trial information: NCT05432193 .

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Purroy, Noelia, Nicholas Durham, Marc Phillips, Maureen M. Hattersley, Lindsey Jung, Diwakar Davar, Dmitriy Zamarin, Tanner M. Johanns i Igor Puzanov. "Abstract CT218: First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors". Cancer Research 82, nr 12_Supplement (15.06.2022): CT218. http://dx.doi.org/10.1158/1538-7445.am2022-ct218.

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Abstract Background: Oncolytic viruses selectively infect tumors and activate antitumor immune responses via innate and adaptive pathways, leading to immunogenic cell death and potentiating the efficacy of immune checkpoint inhibitors. MEDI9253 is a recombinant Newcastle disease virus (NDV) that incorporates a human transgene encoding the immunostimulatory cytokine interleukin (IL)-12, which leads to tumor cell lysis and localized IL-12 expression. Preclinical studies show that MEDI9253 induces PD-L1 expression and recruits innate and adaptive immune cells to the tumor microenvironment (TME) and indicate that its antitumor activity is enhanced by concurrent PD-L1 blockade. This clinical study is evaluating intravenous (IV) MEDI9253 in combination with the anti-PD-L1 antibody durvalumab in patients with selected advanced solid tumors. Methods: This is a phase I, multicenter, open-label, dose escalation and dose expansion trial (NCT04613492) enrolling patients with microsatellite-stable colorectal cancer (MSS-CRC), renal cell carcinoma (RCC) or melanoma. Eligibility criteria include progressed/refractory disease or intolerance to all prior lines of therapy with proven survival benefit for recurrent/metastatic disease. Patients must have life expectancy ≥12 weeks by GRIm score; histologically documented disease; adequate performance status (ECOG 0-1); adequate organ function; and presence of RECIST v1.1 measurable disease amenable to repeated biopsy. Exclusion criteria include untreated/uncontrolled metastatic CNS involvement. Patients must take precautions to prevent the theoretical risk of NDV transmission to humans and birds. The trial will enroll up to ~192 patients across 30 centers globally. The dose escalation phase will evaluate a single dose of IV MEDI9253 with sequential IV durvalumab, then multiple-dose cohorts of up to 4 ascending dose levels of MEDI9253 with sequential or concurrent durvalumab. The dose expansion phase will include 3 cohorts of ~20 patients, each enrolling a single tumor type. In both phases, durvalumab will be dosed for up to 2 years or until disease progression, clinical deterioration, withdrawal of consent or unacceptable toxicity. Pretreatment and on-treatment tumor biopsies are required for patients in multiple-dose cohorts. The primary objectives are evaluating the safety, tolerability and incidence of dose-limiting toxicities of MEDI9253 and identifying the optimal dose/schedule in combination with durvalumab. Secondary objectives include assessing initial efficacy (response and progression-free survival by RECIST v1.1, and overall survival), pharmacodynamics in the TME, immunogenicity, and pharmacokinetics (viremia and IL-12). The trial is recruiting. Citation Format: Noelia Purroy, Nicholas Durham, Marc Phillips, Maureen M. Hattersley, Lindsey Jung, Diwakar Davar, Dmitriy Zamarin, Tanner M. Johanns, Igor Puzanov. First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors [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 CT218.

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Coupe, Nicholas, Ian B. Walters, Robert A. Kramer, Uzi Gileadi i Mark R. Middleton. "A phase 1 first-in-human dose finding/randomized phase 2 study of IMM60 and pembrolizumab (PEM) in advanced melanoma and non–small cell lung cancer (NSCLC; IMP-MEL)." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 2582. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2582.

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2582 Background: Invariant natural killer T-cells (iNKTs) share features of innate cells (NK-like) and T-cells (can prime and boost an adaptive immune response). The importance of this relatively rare lymphocyte subset has generated increased interest due to its dual ability to have a direct cytotoxic effect on CD1d expressing tumors and also its ability to induce long-lasting antitumor CD8 T cell responses mediated by cross priming and licensing of dendritic cells. Various clinical approaches involving the use of allogenic iNKT cells (both untransduced and CARs) are in development and here we describe initial clinical studies with IMM60, a synthetically derived agonist of iNKT cells which is formulated in a liposome( PORT-2). In preclinical studies, IMM-60 treatment results in maturation of DCs and B cells and a potent stimulation of iNKT cell-derived IFN-g. In efficacy studies, IMM60 demonstrated monotherapy activity in PD-1 resistant models, (eg., B16-F10), up-regulation of PD-L1 expression on cancer cells as a consequence of its priming effect, and was able to overcome resistance to PD-1 antibody therapy. Methods: IMP-MEL is an open-label first-in-man phase 1/2 study, currently enrolling adult subjects with advanced NSCLC and melanoma. IMM60 containing liposomes were administered IV Q3W at 3 escalating dose levels for 6 doses alone or with PEM 200mg Q3W. The study seeks to assess the safety and efficacy of IMM-60 alone and in combination with PEM. Results: 5 subjects have been enrolled in the monotherapy cohort having a median of 3 prior therapies (min 2, max 5). Median age was 64.5 years. No treatment related adverse events have been reported nor any objective disease responses in the evaluable monotherapy subjects (n=3) to date. Conclusions: IMM-60 is well tolerated when administered IV as monotherapy at the doses tested. The liposomal formulation leads to a favorable preliminary safety profile. Full results of the phase 1 will be reported at the meeting with analysis of circulating cytokines and flow cytometric analysis. The trial plans to transition to phase 2 testing IMM60-alone vs PEM monotherapy vs the combination of IMM60 with PEM. Clinical trial information: 80472712.

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Giovannini, I., R. Agarinis, S. Cacioppo, S. Sacco, G. De Marchi, E. DI Poi, A. Zabotti, L. Quartuccio i S. De Vita. "AB0490 PREVALENCE OF RISK FACTORS FOR CARDIOVASCULAR EVENTS, MALIGNANCY OR THROMBOEMBOLIC EVENTS IN RHEUMATOID ARTHRITIS UNDER JAK INHIBITORS IN A REAL-LIFE MONOCENTRIC COHORT". Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 1439.2–1440. http://dx.doi.org/10.1136/annrheumdis-2023-eular.5908.

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BackgroundRheumatoid arthritis (RA) is an inflammatory, autoimmune disease, characterized by joint inflammation that can lead to irreversible joint damage and significant disability. The immunomodulatory therapies have dramatically changed the patient management, and the introduction of Janus kinase inhibitors (JAKi) leads the way to an oral, efficacious treatment for RA. Among JAKi, tofacitinib and baricitinib are considered as pan-JAKi (pJAKi) while upadacitinib and filgotinib as selective JAKi (sJAKi) drugs. However, recent safety issue has been highlighted, and the 2022 update of the EULAR recommendations for the management of RA suggests to consider the use of a JAKi only after risk assessment[1].ObjectivesThis study aims to describe a monocentric experience of JAKi treatment in RA patients in a real-life setting, focusing on the prevalence of emerging risk factors.MethodsPatients diagnosed with RA according to 2010 ACR/EULAR criteria and treated in a routine clinical setting with JAKi were retrospectively recruited from our rheumatologic clinic from May 2017 to August 2022. We evaluated the risk assessment according to the 2022 update of the recommendation, as reported below, to describe a real-life experience in the use of JAKi. In details we evaluated: age (over 65 years), smoking status, cardiovascular risk factors (such as diabetes, obesity, hypertension), risk factors for malignancy (current or previous history of malignancy other than successfully treated non-melanoma skin cancer), risk factors for thromboembolic events (history of myocardial infarction or heart failure, cancer, inherited blood clotting disorders or a history of blood clots, as well as patients taking combined hormonal contraceptives or hormone replacement therapy, undergoing major surgery or immobile).Results205 RA patients treated with JAKi were included in our study. 133 underwent pJAK treatment, and 77 underwent sJAK treatment. Overall, 167 JAKi treatments were started in female patients. 128 were positive for rheumatoid factor, and 102 for anti–citrullinated protein antibody. 96/205 JAKi treatments were started in patients over 65 (46,8%), 45 were smokers (22%), 76 presented cardiovascular risk factors (37%), 20 showed risk for malignancy (9,8%) and 21 for risk factors for thromboembolic events (10,2%). More details are reported in Table 1. At least 2 risk factors were reported in 30,7% of the population, and 11,7% presented at least 3 risk factors.ConclusionThis study highlights the relative high prevalence of risk factors in a real-life population of RA patients treated with JAKi. The clinical effectiveness of JAKi has already been assessed by clinical trial and real-life experience, whereas the safety issue still remains to be further explored. Further studies are needed to define the RA sub-populations at highest risk for safety, and those patients who could benefit from an early JAKi treatment.References[1]Smolen JS et al.Ann Rheum Dis. 2023;82:3-18.Table 1.pJAKi (n=133)sJAKi (n=72)Age over 65 years, n (%)65 (48,8%)31 (43%)Current smoking, n (%)38 (28,6%)7 (9,7%)Major cardiovascular disease, n (%)47 (35,3%)29 (40,3%)Previous malignancy, n (%)16 (12%)4 (5,5%)Previous thromboembolic event, thrombophilia, n (%)12 (9%)9 (12,5%)Acknowledgements:NIL.Disclosure of InterestsIvan Giovannini Speakers bureau: not relevant for this type of study, Roberto Agarinis: None declared, Sofia Cacioppo: None declared, Stefania Sacco: None declared, Ginevra De Marchi: None declared, EMMA DI POI: None declared, Alen Zabotti Speakers bureau: not relevant for this type of study, Luca Quartuccio Speakers bureau: not relevant for this type of study, Salvatore De Vita Speakers bureau: not relevant for this type of study.

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Lowndes, S. A., A. Adams, A. Timms, M. Middleton, C. Hayward, S. D. Reich, A. P. Mazar i A. L. Harris. "Phase I study of ATN-224 in patients (pts) with advanced solid tumours". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 2065. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2065.

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2065 Background: Copper chelation reduces the secretion of many angiogenic factors and reduces tumour growth and microvascular density in animal models. ATN-224 is a second generation analogue of ammonium tetrathiomolybdate, which reportedly can stabilise disease but was limited by the slow onset of copper depletion (50–60 days). Preclinical studies suggest ATN-224 may act primarily by superoxide dismutase 1 (SOD-1) inhibition. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin (Cp), to 5–15 mg/dl (normal 16–60) in 14–21 days, to determine the pharmacokinetic profile, and to evaluate dose-limiting toxicities. Methods: Cohorts of pts were treated with escalating doses of ATN-224, twice daily, until copper depletion, followed by a titrated maintenance dose. Serum Cp was used as a surrogate marker of copper levels and was titrated to a target range of 5–15mg/dL (normal 16–60). Results: 18 pts have received 54 cycles of ATN-224. Tumours were breast (4), renal (2), melanoma (2), colon (2), and a variety of other types (1 each). Pts received ATN 224 loading doses in cohorts of 1 to 6 pts: 150 (1), 210 (2), 240 (1), 270 (6), 300 (5), and 330 mg/day (3). Mean age was 56 yrs (range 37–78) and PS 0–2. Mean baseline Cp was 39.6 (range 22–63 mg/dL). The maximum administered dose was 330 mg/day where grade 3 lethargy was observed in 3 pts. Of the 4 pts at the maximum tolerated dose of 300 mg/day who have currently completed the loading schedule, all 4 have achieved a reduction of Cp to within 10% of the target range within 21 days. Other toxicities at this dose level included sulphur burps (Gr 1), vomiting (Gr 2), neutropenia (Gr 2), and anaemia (Gr 3). Toxicities reduced in the second and subsequent cycles when doses were titrated downward to maintain Cp levels in target range. PK data indicate greater absorption of ATN 224 and more rapid reduction in Cp with concurrent administration of a proton pump inhibitor. Stable disease of >6 months was observed in 4 pts. Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/day leads to a reduction of serum Cp levels to 20% normal within 21 days. This will be the recommended starting dose level for phase II study. (Sponsored by Cancer Research UK; funded by Attenuon, LLC). [Table: see text]

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Knorr, David, Jeffrey Ravetch, Gabriela D’Andrea, Linda Vahdat, Christopher Klebanoff i Mark Robson. "496 Toxicity of an Fc engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable anti-tumor immunity in patients". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (listopad 2021): A528. http://dx.doi.org/10.1136/jitc-2021-sitc2021.496.

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BackgroundCurrently approved immune-based therapeutics primarily block inhibitory T cell checkpoints. Alternative approaches involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. CD40 provides a central mechanism for the activation dendritic cells and is well established in pre-clinical models. Despite its promise, multiple clinical trials with agonistic anti-CD40 antibodies have reported minimal clinical responses and systemic toxicity. Efficient CD40 agonism requires receptor multimerization which we achieved by engineering the human anti-CD40 antibody CP-870,893 with 5 point-mutations in the Fc domain selectively increasing its binding to human FcyRIIB (herein ”2141-V11”). The re-engineered antibody demonstrated significantly enhanced anti-tumor activity as compared to its parental IgG2 version using a mouse model carrying human Fcy receptors (FcyR) and human CD40 (hFcyR/hCD40) in place of their mouse homologues.1 When given systemically, enhanced in vivo activity was accompanied by thrombocytopenia and transaminitis, similar toxicities seen with current clinical anti-CD40 antibodies, resulting from the expression of CD40 on platelets and Kupffer cell activation. As a prelude to clinical studies of 2141-V11 an optimized a dosing and delivery regimen resulting in minimal toxicity with optimal anti-tumor activity was developed, demonstrating that direct intratumoral injection led to potent local and systemic anti-tumor immunity.2MethodsWe performed pre-clinical toxicology testing in macaques and found no toxicity up to 100 mg/kg subcutaneously, in contrast to the toxicity observed in hCD40/hFcyR mice. CD40 agonistic antibodies require engagement by their Fc to FcyRIIB to achieve receptor multimerization and agonistic signaling. This lack of toxicity in macaques resulted from the observation that while 2141-V11 can engage the macaque CD40 molecule it does not engage the macaque inhibitory FcyRIIB, highlighting the importance of matching antibodies with their species specific Fc receptors. Full toxicology results will be reported at the annual meeting. We are now testing intratumoral 2141-V11 in a phase I clinical study using a 3+3 design in patients with solid tumors with injectable cutaneous, subcutaneous, or nodal lesions.ResultsWe have completed the first two cohorts without DLTs. In 5/6 patients with breast cancer the best overall response was stable disease. In one patient with melanoma in-transit disease we saw a complete response in the second dose group. The third dose group is currently enrolling and updated results will be reported at the meeting.Abstract 496 Figure 1Intratumoral 2141-V11 leads to both local and distant anti-tumor responses (melanoma)ConclusionsIntratumoral therapy with the Fc-enhanced CD40 agonist 2141-V11 has been demonstrated to be safe, with promising signs of early activity in both injected and distant non-injected lesions (figure 1).Trial RegistrationNCT04059588ReferencesDahan R, Barnhart BC, Li F, Yamniuk AP, Korman AJ, Ravetch JV. Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement. Cancer Cell 2016;0(0):3755–66.Knorr DA, Dahan R, Ravetch JV. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proceedings of the National Academy of Sciences 2018. Oct 23;115(43):11048–11053.Ethics ApprovalThis study was approved by the Rockefeller University IRB.

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Hamid, Omid, Melissa L. Johnson, Jason Luke, Richard T. Maziarz, Jamie Merchan, Emerson E. Lim, Sandip P. Patel i in. "Abstract CT187: Phase 1 Trial of RTX-240, allogeneic red blood cells engineered to express 4-1BBL and trans-presented IL-15, in patients (Pts) with advanced solid tumors". Cancer Research 82, nr 12_Supplement (15.06.2022): CT187. http://dx.doi.org/10.1158/1538-7445.am2022-ct187.

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Abstract Background: RTX-240 is an allogeneic cellular therapy genetically engineered to express high copy numbers of trimeric 4-1BBL and IL-15/IL-15Rα fusion proteins on the RBC surface membrane. RTX-240 is designed to activate and expand CD8+ memory T cells and NK cells and is restricted to the normal biodistribution of red blood cells to mitigate toxicity. Safety, pharmacodynamic (PD) effects, pharmacokinetics (PK) and preliminary efficacy of RTX-240 were assessed in a Phase 1 study of pts with solid tumors. Methods: Pts with relapsed/refractory solid tumors not eligible for standard therapy were treated with monotherapy RTX-240 in 10 cohorts utilizing 6 dose levels (1x108-5x1010 cells per dose) and 4 different schedules until disease progression or unacceptable toxicity. Peripheral blood and tumor tissue were collected at baseline and on-treatment. Results: As of Dec 3, 2021, 30 pts with solid tumors (median age 58 yr, range 23-80, 17 males, 20 ECOG 1), were treated with single agent RTX-240. Pts had previously received a median of 3 therapies (range, 1-9); 21 pts had received prior PD-1/PD-L1 inhibitor (i) therapy. Common tumor types included NSCLC (n=7), melanoma (n=7), colorectal/lower GI (n=4) and RCC (n=3). Per RECIST v1.1, a confirmed partial response (PR) was observed in 1 pt with anal carcinoma and an unconfirmed PR in a uveal melanoma, both of whom had been previously treated with a PD-1. Disease control (PR or stable disease > 12 weeks) occurred in 11/30 pts (37%), of which 7 had received a prior PD-1 for a median of 8 months. Peripheral blood PD studies demonstrate activation, expansion, and cytotoxic potential (GzB) of both NK and memory CD8+ T cells. Every pt with evaluable samples (n=29) had an increase in at least one of the activation or expansion parameters, and the majority had an increase in all. There was also a clear dose response effect in NK cell numbers and trends in other PD markers. Immune activation was observed by increases in plasma IFN-γ in a subset of patients. On-treatment biopsies in a subset (3/5) of evaluable pts show infiltration of NK and/or T cells into the tumor microenvironment (TME) after RTX-240 dosing. No DLTs or related grade (Gr)>3 AEs were seen. The most common treatment-related AEs (Gr 1-2) were fatigue (n = 6); chills, nausea, decrease in appetite, arthralgia (n =3); and fever, myalgia, dysgeusia, and hyperhidrosis (n=2). Additional Gr 2 irAEs include pneumonitis, adrenal insufficiency, hypothyroidism, and worsening transaminitis. Conclusions: RTX-240 is well tolerated at all tested doses, schedules and routes. The drug leads to activation, expansion and trafficking of two target cells (memory CD8+ T cells and NK cells) into the TME, exhibits a clear dose response effect with NK cells and demonstrates preliminary evidence of anti-tumor activity. Dose escalation continues and a PD-1 inhibitor combination arm is also enrolling. Citation Format: Omid Hamid, Melissa L. Johnson, Jason Luke, Richard T. Maziarz, Jamie Merchan, Emerson E. Lim, Sandip P. Patel, Geoffrey M. Kuesters, Iga Sienczylo, Gilad Gordon, Karen Campbell, Kristin Horton, Laurence Turka, Alexander I. Spira. Phase 1 Trial of RTX-240, allogeneic red blood cells engineered to express 4-1BBL and trans-presented IL-15, in patients (Pts) with advanced solid tumors [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 CT187.

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Allen, Ian Matthew, Yonina Robbie Murciano-Goroff, Leyre Zubiri, Qun Li, Michael Sang Hughes, Marko Velimirovic, Jacqueline N. Chu i in. "Flu vaccination rate of patients with severe immune-related adverse events." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e18234-e18234. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18234.

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e18234 Background: Infection with influenza in adults with cancer carries an increased risk of morbidity and mortality. Vaccination against seasonal influenza (Flu-V) can decrease the incidence of influenza, shorten its course, and reduce influenza-associated morbidity. Recent data has suggested that the administration of the Flu-V to patients on an ICI leads to an exaggerated inflammatory response and an increased risk of irAE. However, this trend was demonstrated in a small cohort of patients with lung cancer. Current recommendation for annual Flu-V in patients treated with ICI is unclear and literature about safety is limited. We compared rates of Flu-V for patients on ICI admitted with severe toxicity vs those patients on ICI who were admitted for reasons other than toxicity. We also evaluated rate of Flu-V among oncology patients who had received non-immunotherapy modalities. Methods: We retrospectively evaluated patients treated with ICI who were admitted to Massachusetts General Hospital from February 5, 2011- June 12, 2017. Patients received ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or a combination in treatment of an advanced solid tumor malignancies including melanoma, NSCLC, SCCHN. Admissions due to irAE were confirmed by review of clinical, radiologic, and pathologic features. Flu-V status was determined by rigorous chart review. Nearest neighbor matching was used to create a control group of cancer patients treated with non-ICI modalities. Descriptive statistics compared rates and timing of Flu-V relative to admission. Statistical significance was determined using Fischer’s Exact Test, p < 0.05. Results: Of 540 patients on ICI, 28% were admitted for irAE, 72% had a non-irAE reason for admission. The rate of Flu-V in the flu season prior to admission for irAE group was lower than for non-irAE (18.5% vs 29.6%; p value = 0.01). There were no differences in vaccination rates within ≤30 days (2.7% vs 3.6%, p = 0.80), ≤90 days (4.0% vs 9.3%, p = 0.05), or ≤180 days of admission (11.9% vs 18.5%, p = 0.07). Flu-V rate overall in patients on ICI was 26.5%. In comparison, Flu-V rate in the nearest neighbor non-immunotherapy oncology patients was 67% (n = 101). Conclusions: Flu-V rates were much lower in patients treated with ICI compared to patients treated with non-ICI modalities. We did not see a higher rate of Flu-V in patients admitted with irAE compared to non-irAE which suggests that Flu-V and severe irAE may not be linked in clinical practice. Additional studies are needed, but Flu-V in patients on ICI holds potential to improve care.

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Fugere, Brad, Jim Zhongning Chen, Farah Mazahreh, Tyler Fugere, Liyan Mazahreh i A. Mazin Safar. "Weight loss (WL) as a predictive factor for immune oncology (IO)." Journal of Clinical Oncology 41, nr 16_suppl (1.06.2023): e14528-e14528. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e14528.

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e14528 Background: WL is an adverse prognostic factor/symptom reported in ~40% cancer (ca) patients (pts) at diagnosis agnostic to site or histologic grade. The mechanism of WL in ca, however, remains elusive. The role of energetic waste in ca WL is doubtful (it neglects likely dietary compensation). On the other hand, lymphocytic activation, a clonal, energetically demanding process is accompanied with anorexia limiting caloric intake which leads frequently to WL if protracted over months as seen in lymphoma (B-symptom) or indecisive immune engagement (Eng) with tuberculosis. WL of > 5% of body weight, was an adverse prognosticator and exclusion criterion in non-small cell lung cancer (NSCLC) chemotherapy (CT) trials, likely due to CT or steroids' abrogation of the putative, limited immune ca containment. We hypothesized that WL in ca reflects months of immune Eng, ineffective as it may be at containing the tumor, but nevertheless representing immune Eng with the ca. Such cases stand the best chance for IO benefit. Notably, IO impact in ca mirrors the 40% of WL in ca pts. Methods: Tumor registry retrieved data from all stage 4 cancers treated with monotherapy IO in our institution. We dichotomized pts to beneficiaries (B) or non-beneficiaries (NB). Bs survive longer than median survival for the respective stage/line of therapy in each ca derived from published trials. To account for missing WL data prior to IO, we reasoned that weight gain of ≥10 lbs (reliably charted over 1 year from IO infusions) is acceptable surrogate for WL and met our criteria. Results: WL in our cohort (n = 53) of Melanoma, NSCLC, renal cell carcinoma, and bladder ca was 43% of B; 10% in NB (ratio > 4:1) rejecting the null hypothesis (p < 0.05). PDL-1, Tumor Mutation Burden, both inconclusive in identifying durable benefit, were limited in our set precluding further analysis. Conclusions: Our results support, though do not prove, that WL identifies the appropriate IO pts. Improved outcome despite a historically-adverse prognosticator (WL); the fact that IO was the only ca therapy used, both support our interpretation. We hope to stimulate others to examine independent larger datasets to confirm this notion and to allow comprehensive subset analyses. For WL to be utilized properly the relevant clinical context is crucial, accounting for GI obstructing ca (esophageal ca), enzymatic anomalies (pancreatic ca), volume fluctuations (cirrhosis), catabolism (prolonged hospitalization), or dental issues, to name a few. Additionally, factors such as tumor bulk, perhaps discerned from the T of TNM staging, deserve examination since more vigorous immune activation against larger targets could produce more impact on appetite and caloric intake. Finally, available clinical trial datasets, not tumor registries, might provide a more crisp, reliable source as we continue this investigation. WL can, with confirmatory work, be clinically incorporated as a predictive factor for IO benefit.

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Chen, Szu-Ying, Ons Mamai i Rosemary Akhurst. "Abstract 3420: Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment". Cancer Research 82, nr 12_Supplement (15.06.2022): 3420. http://dx.doi.org/10.1158/1538-7445.am2022-3420.

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Abstract Our goal for this study is to use a mouse genetics approach to identify host germline genetic variants that determine therapeutic responses to cancer immunotherapy (IMT) and to validate these findings in cancer patients treated with α-PD-1. The information gathered may lead to drug targets that potentiate IMT responses and genetic markers may contribute to risk scores for response to IMTs. Immune Checkpoint blockade (ICB) therapy leads to remarkable clinical responses, including highly durable complete responses in a fraction of patients. Consequently, α-PD-1/PDL-1 is now first-line therapy for treating melanoma and NSCLC (non-small cell lung carcinoma). However, most patients do not respond to α-PD-1 therapy, and few show systemic adverse effects. There is therefore an unmet need to develop biomarkers and drug targets that will potentiate therapeutic responses to ICBs. Firstly, we found that blockade of active TGFβ using therapeutic antibodies synergizes with α-PD-1 therapy to potentiate tumor rejection, thus, we hypothesized that variant genetic modifiers of TGFβ1 may influence outcomes of α-PD-1 therapy. By utilizing Tgfbm3b-C57BL/6 (Tgfbm3b-C57) mice carrying a genetic variation of TGFβ1 to study the anti-tumor response to IMT, we confirmed that Tgfbm3b-C57 potentiated anti-tumor responses to α-PD-1 and to combinatorial α-PD-1/α-TGFβ IMT with higher induction of CD8+ T cell-mediated anti-tumor cytotoxicity. The C57 allele contains gene Adam17 that encodes an amino acid variant, L613V, and a charge change at amino acid 113 (D113N). Protein ADAM17 is a sheddase that involves in TNFα biosynthesis and sheds the TGFβ type I receptor (TβRI) to attenuate TGFβ signaling. To understand the molecular function of the variants, the vectors encoding wildtype (NIH) ADAM17 that carries D113, L613 versus the variant (C57) ADAM17 that has N113, V613, are being transfected and tested for the action on a panel of ADAM17 substrates including TNFα and TβRI on NIH3T3 cell line. We are also investigating whether genetic variation within the syntenic human TGFBM3 locus confers differential survival benefit to patients after α-PD-1 therapy. We will confirm the genetic association of ADAM17 SNPs and screen the TGFBM3b locus from LPIN1 to HPCAL1, and YWHAQ to DDEF2. The dataset includes genome-wide association data from progression-free survival analysis of 2000 NSCLC patients following α-PD-1 therapy. The preliminary data from our initial cohort (n=862) of NSCLC patients on PD-1 inhibitors are currently being evaluated. By investigating the molecular and cellular mechanisms by which Tgfbm loci influence ICB outcomes and addressing the relevance to human cancer patients, this project not only addresses an important basic science question but may ultimately lead to novel biomarkers or drug targets that can improve IMT outcomes and reduce adverse effects. Citation Format: Szu-Ying Chen, Ons Mamai, Rosemary Akhurst. Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment [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 3420.

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Chawla, Sant P., Victoria S. Chua, Erlinda M. Gordon, John Cini, Susan Dexter, Manual DaFonseca, Justus Bingham, Grantham W. Hogeland i Richard T. Kenney. "Abstract CT245: Clinical development of a novel form of interleukin-12 with extended pharmacokinetics". Cancer Research 83, nr 8_Supplement (14.04.2023): CT245. http://dx.doi.org/10.1158/1538-7445.am2023-ct245.

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Abstract Recombinant interleukins (IL) have had limited clinical success due to inefficient tumor targeting and short pharmacokinetics (PK), requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 is a promising cancer treatment due to its activation of T and natural killer (NK) lymphocytes to produce interferon (IFN)-γ, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. To address these issues, we developed a novel platform that delivers either mono- or bifunctional immunomodulator(s) linked to a Fully-Human, Albumin Binding scFv domain (FHAB®), which provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC, an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Excellent tumor growth inhibition was seen using a “cold” immunosuppressive B16F10 melanoma model for comparing the efficacy of IL12-FHAB with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. We are conducting a first-in-human, dose-escalation trial to evaluate the safety and tolerability of SON-1010 (IL12-FHAB) and to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. The study has a traditional 3+3 design, modified to take advantage of the known tachyphylaxis of IL-12 with the introduction of a desensitizing first dose to allow administration of higher maintenance doses. No dose-limiting toxicities have been encountered in the first 3 dose cohorts and the MTD is at least 300 ng/kg. While adverse events seen in other studies of IL-12 have occurred, they have been transient and tolerable, allowing further dose escalation. Increases in IFN-γ were dose-related, controlled, and prolonged. The levels peaked at 24 to 48 hours and returned to baseline after 2 to 4 weeks. Low levels of IL-10 were induced in a dose-dependent manner. No drug-related increase was seen with IL-1β, IL-6, IL-8, or TNF-α and there was no evidence of cytokine release syndrome at these doses. The preliminary geomean elimination half-life (T½) was 122 hrs with first-order kinetics, compared with 12 hrs for SC rhIL-12. The accumulation estimates are within the margin of error and are not likely to be physiologically significant with subcutaneous dosing of SON-1010 every 3 weeks. Eight of 11 patients had stable disease at the first follow-up CT, 4 of whom were progressing at study entry. Two patients were stable at 4 months and 2 had unconfirmed progressive disease; 1 patient remains stable after 8 months on SON-1010 with evidence of tumor regression. SON-1010 may have a positive synergistic effect with an immune checkpoint inhibitor (ICI), particularly with ‘cold’ tumors that over-express SPARC. The next stage of development will be to explore the MTD of SON-1010 in combination with an ICI, then to compare that approach with the standard of care in Phase 2. Citation Format: Sant P. Chawla, Victoria S. Chua, Erlinda M. Gordon, John Cini, Susan Dexter, Manual DaFonseca, Justus Bingham, Grantham W. Hogeland, Richard T. Kenney. Clinical development of a novel form of interleukin-12 with extended pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT245.

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Crespin, Athéna, Pierre-Alain Bandinelli, Clément Le Bescop, Renaud Buffet, Jean De Gunzburg, Fabien Vitry, Gérard Zalcman i Julie Cervesi. "278 Systematic review and meta-analysis evaluating the impact of antibiotic use on clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (listopad 2021): A301—A302. http://dx.doi.org/10.1136/jitc-2021-sitc2021.278.

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BackgroundIn recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs).1–3 Antibiotic (ABX) exposure, that leads to microbiome dysbiosis, was further shown in numerous studies to adversely influence the clinical outcomes of cancer patients treated with ICIs, especially in non-small-cell lung cancer (NSCLC).4–6We published in 2020 a meta-analysis confirming that ABX use could hamper survival of NSCLC patients treated with ICIs.7 The present study aims at updating this prior work by incorporating studies published until July 2021 and by studying new clinical outcomes.MethodsPubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of NSCLC patients treated with ICIs. Studies were included when reporting a hazard ratio (HR) or Kaplan–Meier curves for Overall Survival (OS) or Progression-Free Survival (PFS) based on antibiotic exposure, and/or data on treatment response such as Overall Response Rate (ORR) and Progressive Disease Rate (PD) according to antibiotic exposure. Pooled HRs for OS and PFS and Odds Ratios (OR) for ORR and PD were calculated, as well as HRs for OS and PFS according to different time windows of ABX exposure.ResultsOverall, 35 independent cohorts were included for a total of 12,235 patients. The pooled HRs for OS (12,235 patients) and PFS (5,356 patients) were 1.63 [95% Confidence Interval (CI) 1.37–1.94] and 1.49 [95% CI 1.26–1.76], respectively, confirming a significantly reduced survival in patients exposed to ABX. The subgroup analyses of OS and PFS based on the time window of ABX exposure (figures 1 and 2) suggest a harmful effect of ABX when taken around ICI initiation. The pooled OR for ORR (1,992 patients) and PD (1,272 patients) were 0.66 [95% CI 0.44–0.99] and 1.98 [95% CI 1.39–2.8], respectively, reflecting both a decreased odd of treatment response and an almost two-fold increased odd of cancer progression among ABX users (figures 3 and 4). These findings confirm the previously reported deleterious effect of ABX on all clinical outcomes (table 1).Abstract 278 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 3Forest plot of odds ratios for overall response rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Figure 4Forest plot of odds ratios for progressive disease rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Table 1Summary of the impact of antibiotic use on all clinical outcomesConclusionsAntibiotics were shown to impair clinical outcomes of NSCLC patients treated with ICIs in this study. Two (non mutually exclusive) mechanisms are increasingly discussed in the literature to explain the role of microbiome on immunotherapy response: the immunomodulatory effects of bacterial molecules,8 and antigenic mimicry between commensal bacteria and tumor antigens cross reactive for the same antigen specific T cells.9 10ReferencesGopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 5 January 2018;359(6371):97–103.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 5 January 2018;359(6371):91–7. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 5 January 2018;359(6371):104–8. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol 1 June 2018;29(6):1437–44.Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 1 Décember 2019;5(12):1774–8.Rounis K, Makrakis D, Papadaki C, Monastirioti A, Vamvakas L, Kalbakis K, et al. Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: results from a prospective, single institution study. PloS One 2021;16(6):e0252537.Lurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer July 2020;15(7):1147–59.Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science 26 March 2021;371(6536):eabc4552.Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 21 août 2020;369(6506):936–42.Bessell CA, Isser A, Havel JJ, Lee S, Bell DR, Hickey JW, et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 23 avr 2020;5(8):135597.

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Togami, Katsuhiro, Sun Sook Chung, Vikas Madan, Christopher M. Kenyon, Lucia Cabal-Hierro, Justin Taylor, Sunhee Kim i in. "Male-Biased Spliceosome Mutations in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Impair pDC Activation and Apoptosis". Blood 136, Supplement 1 (5.11.2020): 13–14. http://dx.doi.org/10.1182/blood-2020-137727.

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive, male-biased (>3:1 M:F) hematologic malignancy in which some patients have bone marrow involvement at diagnosis (50%) and most have tumor formation in the skin (~90%), often preceding marrow disease. The prognosis is poor (median survival of 12-24 months) and there is unmet need for biological insight. TET2, ASXL1, and RNA splicing genes (SRSF2, SF3B1, and ZRSR2) are recurrently mutated in BPDCN. The X chromosome gene ZRSR2 was the most frequently mutated spliceosome gene reported in a prior BPDCN cohort (7 of 24, 29.2%; Taylor, ASH 2013). Our goal was to define the functional consequences of ZRSR2 mutations in BPDCN. First, we confirmed the frequency of ZRSR2 mutations in a larger cohort from the US and Europe; we found ZRSR2 mutations in 24 of 93 (25.8%). Notably, ZRSR2 mutations were almost exclusively in males (23/73 males vs 1/20 females, P=0.019). Next, we compared the global mutation pattern to 30 predefined signatures from >7000 cancers in COSMIC. Analysis of all somatic single nucleotide variants in 11 tumor-normal pairs using whole exome sequencing (tumor was sorted BPDCN cells from marrow) revealed that BPDCN had an ultraviolet (UV)-induced mutation signature (score >0.25 in 6/11 or 55%; Figure 1A). For comparison, we detected the UV signature in melanoma but not in AML from The Cancer Genome Atlas. These data suggest that mutations acquired in the skin stage of BPDCN evolution are retained in subsequent leukemic disease. Next, we performed RNA-sequencing from sorted BPDCN and normal plasmacytoid dendritic cells (pDCs). Differentially expressed genes between BPDCN and pDCs (BCL2, MYB, IRF4, CEP70, IGLL1, GZMB) were similar to those that distinguish BPDCNs from pDCs by bulk and single cell RNA-sequencing. By gene set enrichment analysis (GSEA), BPDCNs were enriched for overexpression of MYC/E2F targets and PI3K/AKT/MTORC1 signaling pathway-associated genes. BPDCNs transcriptomes were also enriched for gene sets associated with RNA splicing machinery and RNA nonsense mediated decay (NMD). To link RNA splicing with functional consequences of ZRSR2 mutations, we generated ZRSR2-knockout BPDCN cells (CAL1) using CRISPR/Cas9. This models primary tumors because ZRSR2-mutant BPDCNs have complete loss of ZRSR2 protein. Activation marker (CD80) upregulation and type 1 interferon secretion after Toll-like receptor (TLR) stimulation with lipopolysaccharide (LPS) or R848 were reduced in ZRSR2-deficient cells. We found similar defective cytokine production in stimulated primary BPDCN cells compared to normal pDCs. After activation, normal pDCs undergo apoptosis in a negative feedback process. In contrast, ZRSR2-knockout, but not control cells, were protected from TLR activation-induced apoptosis. Reexpression of wild-type ZRSR2 in knockout cells restored activation-induced apoptosis (Figure 1B). These data suggested that ZRSR2-mutant BPDCNs have defects downstream of TLR stimulation. By RNA-sequencing, we found that IRF7 mRNA was mis-spliced in all ZRSR2- (2/2), SRSF2- (4/4), and SF3B1- (1/1) mutant BPDCNs compared to those with no mutated splicing gene (4/4). IRF7 (interferon regulatory factor 7) is a transcription factor activated by TLR signaling that is important for pDC activation and apoptosis. The IRF7 mRNA transcript contains a "weak intron" (intron 4) that is subject to intron retention, which leads to NMD and reduced IRF7 protein level in stimulated dendritic cells (Luke, Mol Cell 2019). IRF7 intron 4 was mis-spliced in ZRSR2-, SRSF2-, and SF3B1-mutant BPDCNs. ZRSR2-knockout CAL1 cells had severely impaired ability to upregulate IRF7 after LPS stimulation, which was partially rescued by reepxression of wild-type ZRSR2 (Figure 1C). Expression of constitutively activated IRF7 inhibited growth of both ZRSR2-knockout and control cells, confirming that the inability to activate IRF7 is important for the effect of ZRSR2 loss on TLR agonist-induced growth inhibition. In conclusion, male-biased ZRSR2 mutations are frequent in BPDCN and impair pDC activation and apoptosis, at least in part via TLR-IRF7. These data may explain why BPDCNs have an impaired activation state (Bierd, BCJ 2019). They also suggest that splicing factor mutations affect cell type-specific pathways to promote transformation, underscoring the importance of studying cancer genes in relevant contexts. Figure Disclosures Griffin: Moderna Therapeutics: Consultancy. Ghandi:Monte Rosa Therapeutics: Consultancy; Cambridge Data Science LLC: Current Employment, Current equity holder in private company. Seiler:Remix Therapeutics: Current Employment. Konopleva:Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Eli Lilly: Research Funding; Genentech: Consultancy, Research Funding; Agios: Research Funding; Rafael Pharmaceutical: Research Funding; Sanofi: Research Funding; AbbVie: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Cellectis: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy; Stemline Therapeutics: Consultancy, Research Funding. Pemmaraju:Cellectis: Research Funding; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Plexxikon: Research Funding; Blueprint Medicines: Honoraria; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding. Abdel-Wahab:H3 Biomedicine Inc.: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company. Lane:Qiagen: Consultancy; Abbvie: Research Funding; Stemline Therapeutics: Research Funding.

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Jain, Nitin, Alessandra Ferrajoli, Musa Yilmaz, Philip A. Thompson, Marina Konopleva, Michael R. Green, Deepa Sampath i in. "Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)". Blood 138, Supplement 1 (5.11.2021): 2626. http://dx.doi.org/10.1182/blood-2021-154195.

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Abstract Background: Dysfunction of T cells, NK cells and other immune subsets is common in patients (pts) with CLL. Venetoclax (VEN), a BCL-2 inhibitor and obinutuzumab (OBIN), a CD20 monoclonal antibody (mAb) are approved for pts with CLL (Fischer, NEJM 2019). Atezolizumab, a PD-L1 checkpoint inhibitor (CPI), is approved for melanoma, lung cancer and other solid tumors. Preclinical studies showed synergy of VEN and CD20 mAb with CPI (Kohlhapp, Cancer Discovery 2021; Westin, Lancet Oncology 2014). Clinical studies showed activity of PD1 inhibition in pts with Richter's transformation, but not CLL (Ding, Blood 2017; Jain, ASH 2018). To our knowledge, no prior study has evaluated PD-L1 inhibition in pts with CLL, nor combined CPI, VEN and OBIN. We hypothesized that combined VEN, OBIN and atezolizumab will be synergistic. Methods: This is an investigator-initiated Phase II trial of combined VEN, OBIN and atezolizumab in pts with previously untreated CLL meeting 2008 IWCLL treatment criteria (NCT02846623). Eligibility criteria included age ≥18 years, adequate organ function (total bilirubin ≤1.5 x ULN, ALT and AST ≤2.5 x ULN, creatinine ≤1.5 x ULN). OBIN was given at a flat dose of 100mg IV Cycle (C)1 Day (D)1, 900 mg C1D2, 1000mg on C1D8, 1000mg on C1D15 and then 1000mg on C2-9 D1. Atezolizumab was given at a flat dose of 1680 mg IV (split over 2 days) on C1D3-4 and then C2-9D1-2. VEN was initiated at the start of C3 with the weekly dose-escalation (20mg daily to a target dose of 400mg daily) and continued daily until end of C14 (total 12 cycles of VEN). All pts stopped therapy at the end of C14. Response assessments were done with CT imaging and bone marrow aspirate/biopsy with MRD assessment (multi-color flow cytometry; sensitivity 10 -4) at the end of C2 (prior to VEN initiation), end of C6, end of C9, and end of C14. Results: From July 2019 to December 2020, a total of 26 pts were enrolled. The median age was 60 years (range, 21-74). The baseline characteristics are shown in Table 1. A total of 19/26 (73%) had unmutated IGHV gene. Though the study did not restrict pts with del(17p) or mutated TP53, no pt in the current cohort had del(17p)/ mutated TP53. A total of 14 (54%) pts had a baseline lymph node >5cm. The median follow-up is 13.3 months. One pt came off study in C1 (details below). A total of 25 pts initiated VEN. The TLS risk categories at the start of C1 were high (n=9, 36%), medium (n=12, 48%), and low (n=4, 16%). After 2 cycles of OBIN and atezolizumab (prior to VEN initiation), the majority of pts had downgrading of TLS risk category [high (n=2, 8%), medium (n=3, 12%), and low (n=20, 80%)]. After C6 (about 3 cycles of VEN 400mg daily), bone marrow undetectable (U)-MRD rate was 19/25 (76%); 4/25 (16%) had low+ MRD and 2/25 (8%) had high+ MRD. After C9 (about 6 cycles of VEN 400mg daily), among the 21 pts (4 pts have not reached this time-point), the bone marrow U-MRD rate was 18/21 (86%); 2/21 (10%) had low+ MRD and 1/21 (5%) had high+ MRD. A total of 14 pts completed C14 (9 pts have not reached this time-point; 2 pts came off study prior to completing C14, details below); 13/14 (93%) achieved bone marrow U-MRD and 1/14 (7%) has low+ MRD. No patient had disease progression or MRD relapse so far. One pt died (details below). Three pts came off study (one developed retroperitoneal hematoma after receiving enoxaparin for DVT in C1; one developed CPI-induced colitis and removed from the study in C10; one died from COVID-19 pneumonia in C14 while in bone marrow U-MRD remission). Grade 3-4 neutropenia occurred in 14/26 (54%) pts. Grade 3 thrombocytopenia occurred in 5/26 (19%) pts; no pt had G4 thrombocytopenia. A total of 4 pts developed CPI-induced toxicities (colitis, G3, n=1; mucositis, G3, n=1; nephritis, G2, n=1; myositis, G2, n=1). A total of 10/25 (40%) pts had dose reduction of VEN, the majority due to neutropenia. Atezolizumab was discontinued early in 3 pts due to CPI-induced toxicities. Laboratory correlative studies including scRNAseq and CyTOF are ongoing. Conclusions: Treatment with combined VEN, OBIN and atezolizumab leads to high rate of early U-MRD remission with 76% bone marrow U-MRD remission at the end of C6 (about 3 cycles of VEN 400mg daily). Four pts had CPI-induced toxicities. The enrollment in this trial continues and updated data and correlative studies will be presented at the ASH meeting. Figure 1 Figure 1. Disclosures Jain: Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Fate Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Konopleva: Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Calithera: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy; Novartis: Consultancy; GSK: Consultancy. Burger: TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Khoury: Stemline Therapeutics: Research Funding; Kiromic: Research Funding; Angle: Research Funding. Kantarjian: Jazz: Research Funding; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Aptitude Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding. Wierda: Karyopharm: Research Funding; Miragen: Research Funding; Acerta Pharma Inc.: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Sunesis: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Loxo Oncology, Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. OffLabel Disclosure: Atezolizumab is not approved for CLL

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Seviiri, Mathias, Richard A. Scolyer, D. Timothy Bishop, Julia A. Newton-Bishop, Mark M. Iles, Serigne N. Lo, Johnathan R. Stretch i in. "Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting". Journal of Translational Medicine 20, nr 1 (5.09.2022). http://dx.doi.org/10.1186/s12967-022-03613-2.

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Abstract Background The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. Objective To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. Methods We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. Results Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90). Conclusion We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

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Castro, María Victoria, Gastón Alexis Barbero, María Belén Villanueva, Luca Grumolato, Jérémie Nsengimana, Julia Newton-Bishop, Edith Illescas, María Josefina Quezada i Pablo Lopez-Bergami. "ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation". Journal of Biomedical Science 28, nr 1 (13.11.2021). http://dx.doi.org/10.1186/s12929-021-00776-w.

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Abstract Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Results Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. Conclusion We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.

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Farlow, Janice L., Scott A. McLean, Nithin Peddireddy, Carol R. Bradford, Kelly M. Malloy, Chaz L. Stucken, Kyle K. VanKoevering, Matthew E. Spector i Andrew J. Rosko. "Impact of Completion Lymphadenectomy on Quality of Life for Head and Neck Cutaneous Melanoma". Otolaryngology–Head and Neck Surgery, 20.04.2021, 019459982110074. http://dx.doi.org/10.1177/01945998211007442.

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Objective Recent randomized data suggest that completion lymph node dissection after a positive sentinel lymph node biopsy (SLNB) improves locoregional control but does not improve survival for melanoma patients. Locoregional recurrences of head and neck cutaneous melanoma (HNCM) may result in significant morbidity. A better understanding of morbidity is thus important to inform decisions about whether to pursue completion neck dissection (ND). Study Design Cross-sectional study. Setting Academic tertiary care hospital. Methods Clinical data were collected for patients with HNCM seen between 2016 and 2019 who were at least 1-year disease free. Each patient completed the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (SLANSS), Neck Dissection Impairment Index, and SF-36 (Short Form–36). Scores were compared by surgical treatment: wide local excision (WLE) only, SLNB, and ND. Univariate and multivariable regression was performed. Results Of 474 patients, 140 returned questionnaires (29.5% response rate; WLE, n = 49; SLNB, n = 76; ND, n = 15). No significant differences in SLANSS or Neck Dissection Impairment Index scores were found between the WLE and SLNB groups. SLANSS scores differed by 2 SD ( P = .001) in the ND cohort, which had a 36% rate of neuropathy. Neck impairment was worse by 1 SD ( P = .01) in the ND cohort. No differences were found in SF-36 domains. Conclusion Neuropathy and neck impairment are components of morbidity after ND. These risks must be balanced with potential morbidity of locoregional recurrence in HNCM.

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Urbanski, Alexander, Julia Minnemann, Cornelia Mauch, Thomas Schmidt, Nicole Kreuzberg, Max Schlaak, Christiane J. Bruns, Dirk L. Stippel i Roger Wahba. "Oligometastatic disease and visceral resections in advanced malignant melanoma: a propensity-matched analysis". Langenbeck's Archives of Surgery 408, nr 1 (21.01.2023). http://dx.doi.org/10.1007/s00423-023-02804-9.

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Abstract Purpose Malignant melanoma is among the tumours with the highest increase in incidence of solid tumours in Germany. While most patients are diagnosed at an early stage and show a good prognosis, advanced stages of malignant melanoma are accompanied with a poor prognosis and limited treatment options. Comparable to other tumour entities, the resection of visceral metastases could lead to a better prognosis. Supplementary, the subgroup of oligometastatic patients might benefit from surgical therapy to a greater extent. Methods This retrospective study analysed 351 patients treated between 2006 and 2017 at the University Hospital of Cologne. A total of 121 patients showed visceral metastases, with which we compared patients with a diffuse tumour spread to patients in an oligometastatic state. Furthermore, we evaluated the effect of visceral resection of oligometastatic, malignant melanoma. Results Our analysis showed that patients with an oligometastatic malignant melanoma had a significantly better prognosis than patients with a diffuse pattern of metastases, if they showed visceral metastases. Furthermore, the resection of visceral metastases leads to a significant gain in median overall survival time (13.6 vs. 34.2 months) and in progression-free survival (9.6 vs. 3.8 months). Conclusion The resection of visceral metastases is a rational treatment option in advanced malignant melanoma. Although our study is limited by a small cohort of patients (n = 18), we believe that the resection of visceral metastases will be fundamental in the treatment of malignant melanoma. In particular, patients in an oligometastatic stage could be an eligible group for surgical treatment.

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Zhang, Wancong, Xuqi Xie, Zijian Huang, Xiaoping Zhong, Yang Liu, Kit-Leong Cheong, Jianda Zhou i Shijie Tang. "The integration of single-cell sequencing, TCGA, and GEO data analysis revealed that PRRT3-AS1 is a biomarker and therapeutic target of SKCM". Frontiers in Immunology 13 (23.09.2022). http://dx.doi.org/10.3389/fimmu.2022.919145.

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IntroductionSkin cutaneous melanoma (SKCM) is the world’s fourth deadliest cancer, and advanced SKCM leads to a poor prognosis. Novel biomarkers for SKCM diagnosis and prognosis are urgently needed. Long non-coding RNAs (lncRNAs) provide various biological functions and have been proved to play a significant role in tumor progression. Single-cell RNA sequencing (scRNA-seq) enables genome analysis at the single-cell level. This study explored prognostic lncRNAs in SKCM based on scRNA-seq and bulk RNA sequencing data.Materials and methodsThe TCGA cohort and melanoma samples in the GEO database (GSE72056, GSE19234, GSE15605, GSE7553, and GSE81383) were included in this study. Marker genes were filtered, and ensemble lncRNAs were annotated. The clinical significance of selected lncRNAs was verified through TCGA and GEO dataset analysis. SiRNA transfection, wound−healing and transwell assays were performed to evaluate the effect of PRRT3-AS1 on cellular function. Immune infiltration of the selected lncRNAs was also exhibited.ResultsA 5-marker-lncRNAs model of significant prognostic value was constructed based on GSE72056 and the TCGA cohort. PRRT3-AS1 combined with DANCR was then found to provide significant prognostic value in SKCM. PRRT3-AS1 was filtered for its higher expression in more advanced melanoma and significant prognosis value. Cellular function experiments in vitro revealed that PRRT3-AS1 may be required for cancer cell migration in SKCM. PRRT3-AS1 was found to be related to epithelial-mesenchymal transition (EMT) signaling pathways. DNA methylation of PRRT3-AS1 was negatively related to PRRT3-AS1 expression and showed significant prognosis value. In addition, PRRT3-AS1 may suppress immune infiltration and be involved in immunotherapy resistance.ConclusionPRRT3-AS1 may be a diagnostic and prognostic biomarker of SKCM.

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Xu, Zhangling, Xia Lv, Wenwen Xu, Yan Ye, Xiaodong Wang, Shuang Ye, Huihua Ding i Wanlong Wu. "Spontaneous Intramuscular Hemorrhage in Anti-MDA5 Positive Dermatomyositis: A Case Series and Literature Review". Frontiers in Medicine 8 (24.01.2022). http://dx.doi.org/10.3389/fmed.2021.802753.

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ObjectiveSpontaneous intramuscular hemorrhage (SIH) is a rare but life-threatening complication associated with dermatomyositis (DM). This study reported a case series of SIH associated with DM. In addition, the characteristics and prognostic effects for this complication were analyzed based on literature review.MethodsWe reported seven cases of anti-melanoma differentiation-associated gene five positive dermatomyositis (MDA5+DM) complicated by SIH in our single-center cohort, and a comprehensive literature review was performed. Clinical characteristics, treatment, and outcome data of all eligible reported cases were summarized. Potential prognostic effects were identified by comparisons between the deceased and survivors.ResultsAmong cumulatively reported patients with DM patients and SIH, the overall mortality was 60.9% (14/23) (including our cases). Fourteen out of nineteen (73.7%) hemorrhagic events occurred within 6 months of disease onset. Anti-MDA5 antibody predominated in those myositis-specific antibodies available cases (8/10), although patients with positive anti-NXP2 and anti-Mi2 have also been documented. Iliopsoas (52.2%, 12/23) was the most frequently involved bleeding location. Bleeding in deep muscles was identified to be associated with poorer prognosis. The mortality of patients with DM and deep muscular hematoma (non-palpable) (80%, 12/15) was significantly higher than that of patients with only superficial muscular hematoma (palpable) (25%, 2/8) (p =0.023).ConclusionSpontaneous hematoma in non-palpable deep muscles probably leads to excess mortality in dermatomyositis, particularly for those with anti-MDA5 antibody, which often occurs within 6 months of disease onset. Clinicians should be vigilant to this rare but potentially fatal complication and carefully balance the risks and benefits of prophylactic anti-thrombotic treatment.

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Vereecke, Gertjan, Justine Defreyne, Dorien Van Saen, Sarah Collet, Jo Van Dorpe, Guy T'Sjoen i Ellen Goossens. "Characterisation of testicular function and spermatogenesis in transgender women". Human Reproduction, 30.11.2020. http://dx.doi.org/10.1093/humrep/deaa254.

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Abstract STUDY QUESTION Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? SUMMARY ANSWER Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. WHAT IS KNOWN ALREADY Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. PARTICIPANTS/MATERIALS, SETTING METHODS The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. MAIN RESULTS AND THE ROLE OF CHANCE Suppressed testosterone levels (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. LIMITATIONS, REASONS FOR CAUTION Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. WIDER IMPLICATIONS OF THE FINDINGS HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. STUDY FUNDING/COMPETING INTEREST(S) D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. TRIAL REGISTRATION NUMBER N/A.

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Peleva, Emilia, Yue Chen, Hasan Rizvi, Catherine Harwood i Jun Wang. "010 Enhanced outcome prediction in cutaneous squamous cell carcinoma using deep-learning and computational histopathology (cSCCnet)". British Journal of Dermatology 188, Supplement_4 (czerwiec 2023). http://dx.doi.org/10.1093/bjd/ljad113.010.

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Abstract Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer and leads to a significant disease burden. Although metastases occur in < 5% of patients, effective treatments are limited and 5-year survival is poor, with mortality rates equivalent to those of melanoma in some regions of the world. Despite recent advances in understanding the molecular pathogenesis of cSCC, patient risk stratification is limited and based on clinicopathological staging, with few validated prognostic biomarkers available to guide management [de Jong E, Lammerts MUPA, Genders RE, Bowes Bavinck JN. Update of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2022; 36(Suppl. 1):6–10]. In this study, we aimed to use artificial intelligence technology to develop a deep learning model using digitized whole-slide images of cSCC to quantify the risk of metastasis. Routine haematoxylin and eosin-stained slides of 256 primary cSCCs from immunocompetent patients at four collaborating centres were scanned. The area of interest encompassing tumour and peritumoral stroma was annotated, and 512 × 512 pixel tiles were generated from each slide. High-quality tiles (containing sufficient tumour content) were pooled together, with patient-level labels inherited by tiles. We trained multiple models using an 80:10:10 split for training, validation and testing, and the model achieving the highest tile- and slide-level validation accuracy was identified (ResNet50). The final model, namely, cSCCnet, achieved 88% sensitivity, 73% specificity, 64% positive predictive value and 92% negative predictive values on the independent test set. Blinded review of the top predictive tiles by three histopathologists suggested that the predictive features identified by cSCCnet were distinct from histopathological features commonly used by clinicians to estimate metastatic risk. We have demonstrated that it is possible to train a deep learning model using digital pathology to predict the risk of metastasis. cSCCnet surpassed the published performance of currently used staging systems, as well as commercially available gene panel testing (de Jong et al.; Wysong A, Newman JG, Covington KR et al. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2021; 84:361–9). The morphological features and patterns identified by cSCCnet are different from established histopathological high-risk criteria, indicating that this technology can enhance current practice. Although further validation in a prospective cohort is pending, this is an important step toward creating a risk stratification tool that can be incorporated into routine pathology workflows, significantly improving patient outcomes for this common cancer.

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