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Minchom, Anna, Wei Yuan, Mateus Crespo, Bora Gurel, Ines Figueiredo, Andrew Wotherspoon, Susana Miranda, et al. "Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab." Journal for ImmunoTherapy of Cancer 8, no. 1 (March 2020): e000713. http://dx.doi.org/10.1136/jitc-2020-000713.
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BackgroundThis case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.Case presentationA 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1.ConclusionThis case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights.
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Mahadevan, Daruka, Li Ma, Kai Treuner, Jenna Wong, and Catherine Schnabel. "330 Integration of molecular cancer classification and next-generation sequencing to identify metastatic patients eligible for immune checkpoint inhibitors." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A356. http://dx.doi.org/10.1136/jitc-2021-sitc2021.330.
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BackgroundImmune checkpoint inhibitors (ICIs) have improved patient outcomes and are a new standard of care for treating a variety of cancers. Eligibility for ICIs is established through determination of tumor type and use of predictive biomarkers. PD-L1, microsatellite instability (MSI), and tumor mutation burden (TMB) are FDA-approved predictive biomarkers for ICI therapies. However, the validity of these biomarkers remains controversial, as studies have shown a failure to predict ICI response in many cancer types.1 2 The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with ambiguous diagnoses. CancerTYPE ID provides critical cancer type identification to guide ICI treatment eligibility and selection. In the current study, analyses integrating tumor type with multimodal biomarker testing for PD-L1 and TMB were evaluated to identify patients for ICI eligibility.MethodsMOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of CancerTYPE ID results from 2572 patients with tumor-specific multimodal biomarker testing by next-generation sequencing for TMB and immunohistochemistry for PD-L1. The Cochran-Mantel-Haenszel test was used to evaluate the relationship between PD-L1 and TMB across tumor types.ResultsTumor type was determined in 2377 of 2572 cases (92.4%), comprising 27 different tumor types including 14 tumor types with FDA-approved ICI therapies. Among the top 20 tumor types, PD-L1 was present in a larger proportion of tumors (weighted mean=78.9%, range=58.3%–100%) versus TMB (20.9%, 0%–72.7%) (figure 1). Varying expression levels of PD-L1 and TMB were noted across tumor types (Figure 1), and no relationship between PD-L1 and TMB (P=0.15) was observed. Prevalence of high TMB in melanoma (42.9%) and lung adenocarcinoma (38.9%), which are more likely to respond to ICI treatment, are consistent with published data; however, prevalence of high TMB in mesothelioma (20.0%), sarcoma (23.6%) and prostatic adenocarcinoma (33.3%), which are not likely to respond to ICI treatment, are higher than previously reported.3Abstract 330 Figure 1Prevalence of PD-L1 expression and high TMB in the 27 identified tumor typesConclusionsTumor type classification and cellular context are critical for ICI eligibility. CancerTYPE ID successfully differentiated 14 ICI-eligible tumor types from 13 non-ICI-eligible tumor types. Further, since there is no relationship between PD-L1 and TMB for different tumor types, accurate tumor type identification is necessary to select the most appropriate biomarker. This highlights the clinical utility of CancerTYPE ID combined with multimodal biomarker testing to guide ICI treatment and predict response based on tumor type identification, which may improve outcomes in patients with metastatic cancer.ReferencesMcGrail DJ, Pilié PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol 2021;32(5):661–672.Gjoerup O, Brown CA, Ross JS, et al. Identification and utilization of biomarkers to predict response to immune checkpoint inhibitors. AAPS J 2020;22(6):132.Yarchoan M, Albacker LA, Hopkins AC, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 2019;4(6):e126908.
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Sokol, Ethan, Natalie Danziger, Dean Pavlick, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Douglas I. Lin, et al. "Clinically aggressive malignancies associated with STK11 germline mutations (STK11GCa): A comprehensive genomic profiling (CGP) study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3558. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3558.
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3558 Background: Germline mutations in the STK11 ( LKB1) mTOR pathway gene are associated with Peutz-Jehger’s Syndrome and a variety of malignancies of variable clinical aggressiveness. Recent evidence also links STK11 inactivation with failure to benefit from anti-cancer immune checkpoint inhibitor (IO) therapy in NSCLC. Methods: Using hybrid capture based CGP on extracted tumor DNA and a published “somatic-germline-zygosity” SGZ data analysis algorithm on 212,470 samples of clinically advanced malignancies, we identified 103 (0.05%) STK11GCa inactivating base substitutions or indels. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 57 (55%) STK11GCa cases were NSCLC, 7 (7%) STK11GCa cases each were CRC, breast, pancreatic and unknown primary carcinomas, and 3 (3%) were gynecologic cancers. Amongst all samples included in this analysis, STK11 germline alterations were found in 0.15% NSCLC, 0.03% CRC, 0.03% breast, 0.08% pancreas, 0.06% unknown primary carcinoma and 0.03% of gynecologic cancers. Additional malignancies harboring STK11GCa included melanoma, gastroesophageal, HNSCC, bladder, HCC, lymphoma and mesothelioma. In STK11GCa, the median patient age at sequencing was 61 years (range 2 to > 89 years); gender distribution was 52% female and 48% male. STK11GCa cases had a median of 6.5 genomic alterations (GA)/tumor and KEAP1, another IO resistance gene, was co-altered in 10%. Currently untargetable GA were detected in TP53 (50%), KRAS (38% with 9% in potentially targetable G12C), CDKN2A (32%), CDKN2B (22%), SMARCA4 (19%), MYC (11%), and APC (10%). Potentially targetable GA, which have also been linked in some studies to IO efficacy, included GA in BRAF (10%), EGFR (9%) and PBRM1 (4%). No targetable gene rearrangements or fusions were identified. No MSI High cases were identified. The median TMB was 5 mut/Mb with 23 % >10 mut/Mb and 4% >20 mut/Mb. 15% of 20 evaluated STK11GCA cases were PD-L1 high (>50% tumor cell staining). Conclusions: STK11GCa include a wide variety of primary tumors with a paucity of co-occurring targetable GA. Although these tumors have significant PD-L1 staining and a subset harbor other markers of potential IO efficacy, the inactivated STK11 in these tumors may contribute to IO resistance and lack of responsiveness to immunotherapies.
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Lujambio, Amaia. "The more (mutations), the better." Science Translational Medicine 11, no. 477 (January 30, 2019): eaaw5320. http://dx.doi.org/10.1126/scitranslmed.aaw5320.
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Hsiehchen, David, Magdalena Espinoza, Cristina Valero, Chul Ahn, and Luc G. T. Morris. "Impact of tumor mutational burden on checkpoint inhibitor drug eligibility and outcomes across racial groups." Journal for ImmunoTherapy of Cancer 9, no. 11 (November 2021): e003683. http://dx.doi.org/10.1136/jitc-2021-003683.
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The FDA approval of immune checkpoint inhibitors for cancers with tumor mutation burden (TMB) of at least 10 mut/Mb is postulated to reduce healthcare disparities by broadly expanding treatment eligibility. In a cohort of 39,400 patients with available genomic and race data, black and Asian patients were less likely to have TMB-high cancers in multiple types of malignancies based on the currently approved cut-off. Decreasing TMB thresholds preferentially increased the eligibility of minority patients for immune checkpoint inhibitors while retaining predictive value of treatment benefit in a cohort of immune checkpoint inhibitor treated patients. This study highlights differing distributions of TMB-high cancers between racial groups and provides guidance in developing more rational eligibility criteria for immune checkpoint inhibitors.
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An, Ho Jung, Hong Jae Chon, and Chan Kim. "Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors." International Journal of Molecular Sciences 22, no. 17 (August 30, 2021): 9414. http://dx.doi.org/10.3390/ijms22179414.
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As cancer immunotherapy using immune checkpoint inhibitors (ICIs) is rapidly evolving in clinical practice, it is necessary to identify biomarkers that will allow the selection of cancer patients who will benefit most or least from ICIs and to longitudinally monitor patients’ immune responses during treatment. Various peripheral blood-based immune biomarkers are being identified with recent advances in high-throughput multiplexed analytical technologies. The identification of these biomarkers, which can be easily detected in blood samples using non-invasive and repeatable methods, will contribute to overcoming the limitations of previously used tissue-based biomarkers. Here, we discuss the potential of circulating immune cells, soluble immune and inflammatory molecules, circulating tumor cells and DNA, exosomes, and the blood-based tumor mutational burden, as biomarkers for the prediction of immune responses and clinical benefit from ICI treatment in patients with advanced cancer.
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Giordano, Frank A., Marlon R. Veldwijk, Carsten Herskind, and Frederik Wenz. "Radiotherapy, tumor mutational burden, and immune checkpoint inhibitors: time to do the math." Strahlentherapie und Onkologie 194, no. 10 (July 20, 2018): 873–75. http://dx.doi.org/10.1007/s00066-018-1341-z.
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Duchemann, Boris, Jordi Remon, Marie Naigeon, Laura Mezquita, Roberto Ferrara, Lydie Cassard, Jean Mehdi Jouniaux, et al. "Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer." Cancers 12, no. 12 (December 3, 2020): 3625. http://dx.doi.org/10.3390/cancers12123625.
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Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.
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Acosta-Medina, Aldo A., Jithma P. Abeykoon, Surendra Dasari, Antonious Z. Hazim, N. Nora Bennani, Terra Lasho, Aishwarya Ravindran, et al. "Tumor Mutational Burden in Histiocytic Neoplasms." Blood 138, Supplement 1 (November 5, 2021): 3634. http://dx.doi.org/10.1182/blood-2021-153128.
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Abstract Background Histiocytic disorders are rare hematologic neoplasms characterized by their high clinical heterogeneity. Evidence of constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in a number of these disorders has led to the increasing use of BRAF- and MEK-inhibitors as a therapeutic strategy. Response to these therapies is not universal and additional effective treatment options are required. Immune checkpoint inhibitors have proven effective for a wide array of malignancies. Tumor mutational burden (TMB), the total number of somatic pathogenic variants per coding region in a tumor genome, is a clinical biomarker associated with response to immunotherapy. We have previously reported preliminary findings of low TMB in a small cohort of patients with histiocytic neoplasms (Goyal G et al. Blood 2019). In this study, our aim was to confirm the findings in a larger clinical cohort using next generation sequencing studies. Methods A retrospective review of adult patients consecutively seen at Mayo Clinic from 2017 to April 2021 and diagnosis of a histiocytic neoplasm was performed. Electronic records were queried for demographic and laboratory data of all patients who consented to undergo tumor-tissue next-generation sequencing with the Tempus-xT ® or xO ® assay (Chicago, IL), throughout the course of their evaluation. TMB was reported as the number of nonsynonymous mutations per coding area of a tumor genome. TMB across groups was compared via an independent-samples T-test or via analysis of variance and post hoc subgroup testing via Turkey's Test as required. Results Seventy-three patients were included in the study. Individual diagnoses included: Erdheim-Chester disease (ECD) in 31.5% (n=23), including 3 patients with overlap features of ECD and other histiocytoses; Rosai Dorfman disease (RDD) in 28.8% (n=21); Langerhans cell histiocytosis in 21.9% (n=16), histiocytic sarcoma (HS) in 5.5% (n=4), and other histiocytic neoplasms in 12.3% (n=10) including adult xanthogranuloma, xanthoma disseminatum, undifferentiated histiocytoses, and one case of Langerhans cell sarcoma. Median tumor percentage on analyzed samples was 30% (range 10%-90%) and was ≤20% in 29 samples. TMB was <1.0 mutations per megabase (mpMb) in 42.5% (n=31) and >5.0 mpMb in only 6 cases. Median TMB was 1.58 (range 0 - 5.26) for ECD, 1.08 (range 0 - 6.3) for LCH, 0.2 (range 0 - 5.8) for RDD, 3.19 (range 1.67 - 6.8) for HS, and 1.6 (range 0 - 7.5) for other histiocytic neoplasms (Figure 1). No clear association between increasing TMB and number of systems with histiocytic infiltration was observed (Figure 2). A significant increase in TMB was observed among the 5 cases of sarcoma as compared to the rest of the cohort (p=0.014). When not considering sarcomas, no differences were observed in TMB between patients with ECD, LCH, RDD or other histiocytoses (F=0.775; p=0.512). Conclusion In this large cohort of histiocytic disorders, TMB was low compared to that historically seen in other neoplasms though this is likely influenced by tumor purity ≤20% in 29 cases. Only 6 tumors had TMB reports with mpMb above the threshold thought to be associated with an increased likelihood of response to PD-1/PDL1-targeted therapies (>5 mpMb). Our results suggest a low likelihood of response among histiocytic disorders using immune checkpoint inhibitors. Further exploration among malignant histiocytoses (HS and Langerhans cell sarcoma) is warranted given our findings of higher TMB compared with other histiocytic neoplasms. Figure 1 Figure 1. Disclosures Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board.
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Bielska, Agata A., Walid K. Chatila, Henry Walch, Nikolaus Schultz, Zsofia K. Stadler, Jinru Shia, Diane Reidy-Lagunes, and Rona Yaeger. "Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance." Journal of the National Comprehensive Cancer Network 19, no. 2 (February 2021): 130–33. http://dx.doi.org/10.6004/jnccn.2020.7680.
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Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.
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Sicard, Guillaume, Frédéric Fina, Raphaelle Fanciullino, Fabrice Barlesi, and Joseph Ciccolini. "Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy." Pharmaceutics 12, no. 8 (August 11, 2020): 758. http://dx.doi.org/10.3390/pharmaceutics12080758.
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Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given.
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Longo, Vito, Oronzo Brunetti, Amalia Azzariti, Domenico Galetta, Patrizia Nardulli, Francesco Leonetti, and Nicola Silvestris. "Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review." Cancers 11, no. 4 (April 15, 2019): 539. http://dx.doi.org/10.3390/cancers11040539.
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Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
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Hong, Xin, Ryan J. Sullivan, Mark Kalinich, Tanya Todorova Kwan, Anita Giobbie-Hurder, Shiwei Pan, Joseph A. LiCausi, et al. "Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy." Proceedings of the National Academy of Sciences 115, no. 10 (February 16, 2018): 2467–72. http://dx.doi.org/10.1073/pnas.1719264115.
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A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.
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Akhaladze, D. G., G. S. Rabaev, N. V. Zhukov, M. A. Pyatnitskiy, N. S. Gorochov, Y. A. Zhulikov, G. G. Rabaev, A. A. Kasatskiy, I. V. Volodin, and N. V. Myakova. "INITIAL EXPERIENCE IN ESTIMATING TUMOR MUTATION BURDEN IN PEDIATRIC HEPATOCELLULAR CARCINOMA." Pediatria. Journal named after G.N. Speransky 100, no. 3 (May 28, 2021): 193–99. http://dx.doi.org/10.24110/0031-403x-2021-100-3-193-199.
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The level of tumor mutation burden (TMB) is a predictive factor of immune checkpoints that determines the potential effectiveness of immune checkpoint inhibitors and indications for their prescription regardless of the type of tumor in adults and children. However, the prevalence of tumors with high TMB in the pediatric population has not been well studied. Objective of the research: to assess the detection frequency of high TMB (>10 mutations per megabase) in pediatric hepatocellular carcinoma (HCC). Materials and methods of research: Next Generation Sequencing, Ion AmpliSeq™ Comprehensive Cancer Panel (409 genes) of tumor DNA samples from 4 children with HCC was performed. The calculation of the mutational load was carried out according to the work of Z.R. Chalmers et al. Results: out of 4 analyzed samples, TMB levels have lower cut-off value than needed for the immunity checkpoint inhibitors for 2 patients to administer: 5,9 mut/MB (primary tumor), 9,2 mut/MB (metastasis), while in 2 other patients the TMB has level above the threshold – 10,9 mut/MB (primary tumor) and 48,5 mut/MB (relapse metastasis), respectively. Conclusion: this paper presents the initial experience of estimation of the TMB level in children with HCC. In our case series report, the level allowing the prescription of immunotherapy (>10 mut/MB) was observed in 2 patients. Further research on a larger cohort of patients is useful to assess the role of mutational burden in disease prediction and effectiveness of immunotherapy.
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Patel, Amol, Dharmesh Soneji, Purvish Parikh, and Manish Kumar. "Biomarkers in immuno-oncology: A review article." International Journal of Molecular & Immuno Oncology 4 (May 20, 2019): 41–49. http://dx.doi.org/10.25259/ijmio-4-041.
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Immunotherapy is the new addition to the armamentarium against cancer. Role of immune checkpoint inhibitors is proven, but with limitations of benefit in around 20% of the patients. The cost of therapy and to some extent the toxicities are deterrent for generalized use. Biomarker is urgently needed to rationalize the use of immunotherapy. Tumor mutational burden, programmed death-ligand 1 expression, microsatellite instability, tumor-infiltrating lymphocytes, T-cell repertoire, and various other biomarkers have shown early promise in predicting response and benefit from immune checkpoint inhibitors. Majority of studies are limited by their retrospective nature, small number, and lack of prospective validation in large cohorts. Precision oncology is desired at every level including patients, doctors, and health-care system of a nation. Here, we concisely reviewed literature.
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El-Sayes, Nader, Alyssa Vito, Omar Salem, Samuel Tekeste Workenhe, Yonghong Wan, and Karen Mossman. "A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner." International Journal of Molecular Sciences 23, no. 3 (February 3, 2022): 1754. http://dx.doi.org/10.3390/ijms23031754.
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Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8+ and CD4+ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3−/− mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner.
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Mazloom, Anita, Nima Ghalehsari, Victor Gazivoda, Neil Nimkar, Sonal Paul, Peter Gregos, Janice Rateshwar, and Uqba Khan. "Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies." Journal of Clinical Medicine 9, no. 8 (August 6, 2020): 2533. http://dx.doi.org/10.3390/jcm9082533.
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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.
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Valente, Ana, Amy Gin, Allison Wells, Kai Ding, and Kathleen Moore. "Exploring tumor mutational burden status and clinical benefit of immune checkpoint inhibitors in endometrial cancer." Gynecologic Oncology 164, no. 1 (January 2022): 3–4. http://dx.doi.org/10.1016/j.ygyno.2021.10.046.
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Kim, Jong Yeob, Andreas Kronbichler, Michael Eisenhut, Sung Hwi Hong, Hans J. van der Vliet, Jeonghyun Kang, Jae Il Shin, and Gabriele Gamerith. "Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis." Cancers 11, no. 11 (November 15, 2019): 1798. http://dx.doi.org/10.3390/cancers11111798.
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Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.
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Rauterkus, Grant, Agreen Hadadi, Reagan Barnett, Caroline Weipert, Leylah Drusbosky, Xin Gao, Michael B. Lilly, et al. "Blood-based tumor mutational burden from circulating tumor DNA and immune checkpoint inhibitors in advanced prostate cancer." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 165. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.165.
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165 Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]
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Corrò, Claudia, Valérie Dutoit, and Thibaud Koessler. "Emerging Trends for Radio-Immunotherapy in Rectal Cancer." Cancers 13, no. 6 (March 18, 2021): 1374. http://dx.doi.org/10.3390/cancers13061374.
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Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.
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C Guven, Deniz, Taha K. Sahin, Omer Dizdar, and Saadettin Kilickap. "Predictive biomarkers for immunotherapy efficacy in non-small-cell lung cancer: current status and future perspectives." Biomarkers in Medicine 14, no. 14 (October 2020): 1383–92. http://dx.doi.org/10.2217/bmm-2020-0310.
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In recent years, immune checkpoint inhibitors have rapidly changed treatment paradigms and have been pivotal for the treatment of advanced NSCLC patients. However, many patients don't respond to immunotherapy, and toxicities are a concern. Mounting evidence suggests that PD-L1 expression and tumor mutational burden are useful biomarkers in NSCLC and widely used in clinical practice. Given various limitations of PD-L1 and tumor mutational burden, many candidate biomarkers have emerged. From these biomarkers, peripheral blood-based biomarkers are promising options for the prediction of immunotherapy efficacy with ease of access, repeatability and low cost. This review provides an overview of recent developments on the biomarkers in immunotherapy efficacy together with comments on future perspectives.
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Ottini, Arianna, Pierangela Sepe, Teresa Beninato, Mélanie Claps, Valentina Guadalupi, Elena Verzoni, Patrizia Giannatempo, Giulia Baciarello, Filippo de Braud, and Giuseppe Procopio. "Biomarker-driven immunotherapy for precision medicine in prostate cancer." Personalized Medicine 19, no. 1 (January 2022): 51–66. http://dx.doi.org/10.2217/pme-2021-0079.
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Although immunotherapy has recently revolutionized standard of care in different cancer types, prostate cancer has generally failed to show dramatic responses to immune checkpoint inhibitors. As in other tumors, the goal in prostate cancer is now to target treatments more precisely on patient’s individual characteristics through precision medicine. Defects in mismatch repair, mutations in the exonuclease domain of the DNA polymerase epsilon ( POLE), high tumor mutational burden and the presence of biallelic loss of CDK12 among others, are predictive biomarkers of response to immunotherapy. In the present review, we summarize the evolving landscape of immunotherapy in prostate cancer, including precision approaches and strategies to define classes of responsive patients and scale up resistance to immune checkpoint inhibitors.
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Citra Wahyudin, Hendris Utama, Afriani Afriani, Fenty Anggrainy, and Sabrina Ermayanti. "Immunotherapy in Lung Cancer: A Narrative Literature Review." Bioscientia Medicina : Journal of Biomedicine and Translational Research 7, no. 1 (March 2, 2023): 3024–30. http://dx.doi.org/10.37275/bsm.v7i1.755.
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Lung cancer is the most common cause of death from cancer in both men and women worldwide. Cancers with low immunogenicity often do not present antigens, so immune responses can be avoided. Uncontrolled growth of tumor cells occurs due to various factors such as activation of immunosuppressive mechanisms, induction of various immunosuppressive cells, and expression of immune checkpoint molecules. The development of lung cancer management has progressed since the discovery of molecular-based target therapy and immunotherapy. The high expression of tumor mutational burden in lung cancer indicates high immunogenicity in lung cancer. Various immunological mechanisms involving programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been developed for the treatment of lung cancer by utilizing immune system modulation. Nivolumab is the first approved immunotherapy for lung cancer, followed by pembrolizumab, atezolizumab, and durvalumab. The use of immunotherapy involving immune checkpoint inhibitors is an important breakthrough in the management of cancer, including lung cancer. This literature review aimed to describe immunotherapy in lung cancer that focuses on immune checkpoint inhibitors anti-PD-1 and anti-PD-L1.
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Bailey, Nathanael G. "Visualization of the Effect of Assay Size on the Error Profile of Tumor Mutational Burden Measurement." Genes 13, no. 3 (February 26, 2022): 432. http://dx.doi.org/10.3390/genes13030432.
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Tumor mutational burden (TMB) refers to the number of somatic mutations in a tumor per megabase and is a biomarker for response to immune checkpoint inhibitor therapy. Immune checkpoint inhibitors are currently approved for tumors with TMB greater than or equal to 10 mutations/megabase. Many laboratories are currently reporting TMB values based upon targeted resequencing panels with limited genomic coverage. Due to sampling variation, this leads to significant uncertainty in the assay’s TMB result, particularly at relatively low TMB levels near the 10 mutation per megabase therapeutic threshold. In order to allow clinicians and laboratorians to explore this uncertainty, we built a novel web application that allows a user to view the potential error of a TMB result given the sequencing panel size. This application also allows the user to explore the effect of incorporating knowledge of a specific tumor type’s typical TMB distribution on the error profile of the TMB result.
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Kinget, Lisa, Oliver Bechter, Kevin Punie, Philip R. Debruyne, Hilde Brems, Paul Clement, Eduard Roussel, et al. "Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors." Current Oncology 28, no. 5 (August 24, 2021): 3227–39. http://dx.doi.org/10.3390/curroncol28050280.
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In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes (BRCA1, BRCA2, CHEK2) responding favorably to ICPIs.
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Koustas, Evangelos, Panagiotis Sarantis, Athanasios G. Papavassiliou, and Michalis V. Karamouzis. "The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors." Biomolecules 10, no. 5 (April 25, 2020): 666. http://dx.doi.org/10.3390/biom10050666.
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The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.
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Cortellini, Alessio. "The Promising Link Among Tumor Mutational Burden, Immune-Related Adverse Events, and Immune Checkpoint Inhibitors Efficacy in SCLC." JTO Clinical and Research Reports 1, no. 4 (November 2020): 100080. http://dx.doi.org/10.1016/j.jtocrr.2020.100080.
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Chen, Nan, Nicole Higashiyama, and Valentina Hoyos. "Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1." Biomedicines 9, no. 12 (December 8, 2021): 1863. http://dx.doi.org/10.3390/biomedicines9121863.
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Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.
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Omuro, Antonio. "Immune-checkpoint inhibitors for glioblastoma: what have we learned?" Arquivos de Neuro-Psiquiatria 80, no. 5 suppl 1 (May 2022): 266–69. http://dx.doi.org/10.1590/0004-282x-anp-2022-s129.
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ABSTRACT Background: Glioblastoma, the most common malignant primary brain tumor, remains a lethal disease with few therapeutic options. Immunotherapies, particularly immune checkpoint inhibitors (ICPi), have revolutionized cancer treatment, but their role in glioblastoma is uncertain. Objective: To review the state of immunotherapies in glioblastoma, with an emphasis on recently published ICPi clinical trials. Methods: In this editorial/opinion article, we critically review results of the first generation of trials of ipilimumab, nivolumab and pembrolizumab in glioblastoma, as well as future directions. Results: Expression of PD-L1 is frequent in glioblastoma, ranging from 60-70% of patients. Phase 1 studies of nivolumab with and without ipilimumab, as well as pembrolizumab, showed no new safety concerns in brain tumors, and no neurotoxicity. However, randomized phase 3 trials of nivolumab showed no survival improvements over bevacizumab in recurrent glioblastoma; no role in newly diagnosed disease as a replacement for temozolomide in unmethylated MGMT promoter tumors; and no benefit as an addition to temozolomide in methylated MGMT tumors. However, studies examining post treatment tumor samples have shown signs of increased immunologic response, and occasional long lasting radiographic responses have been seen. A small study of pembrolizumab suggested a potential role as a “neoadjuvant” treatment in resectable recurrent glioblastoma, while other studies are investigating selection of patients with higher mutational burden and novel agents and combinatorial strategies. Conclusion: Despite initial negative trials, immunotherapy remains of high interest in glioblastoma, and many trials are still ongoing. Improving our mechanistic understanding of the immunosuppression and T cell dysfunction induced by both tumor and the CNS microenvironment remains however crucial for the development of successful immunotherapeutic approaches in this disease.
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Modur, Vishnu, and Fukun Guo. "Tumors bearing defective transcription elongation are immune hot but resistant to immune checkpoint inhibitors." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 119.11. http://dx.doi.org/10.4049/jimmunol.208.supp.119.11.
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Abstract Tumors infiltrated with abundant T lymphocytes are generally thought to respond to immune checkpoint inhibitors (ICI). However, a significant proportion of immune hot tumors are resistant to ICI. The immune nature of such tumors is poorly understood. We recently reported a tumor type that is defective in transcription elongation (TEdef) and irresponsive to ICI in several clinical cohorts. Here, we show that TEdef tumors are unexpectedly infiltrated with cytotoxic T cells (CTLs) in patients and in animal models. Mechanistically, T cell infiltration is facilitated by cytoplasmic DNA/double strand RNA-nucleic acid sensing-TBK1-ccl5/cxcl/9/10 signaling cascade. However, single-cell RNA sequencing combined with flow cytometry reveals that CTLs in TEdef tumors are exhausted. Furthermore, immune suppressive regulatory T cells are enriched in TEdef tumors. ICI treatment of TEdef tumors in mice and human patients fails to further induce T cell infiltration. This study reveals a mechanism underlying inert inflammation and ICI resistance of TEdef tumors. We suggest that TEdef, alongside the surrogate markers of tumor mutational burden and CTLs, should be assessed in immunotherapy-candidate patients. Supported by 5R01CA234038-03
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Saggese, Pasquale, Cesar Martinez, Linh Tran, Raymond Lim, Camelia Dumitras, Tristan Grogan, David Elashoff, et al. "Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer." Cancers 13, no. 14 (July 18, 2021): 3595. http://dx.doi.org/10.3390/cancers13143595.
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Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen N-Methyl-N-Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies.
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Chokshi, Chirayu R., Benjamin A. Brakel, Nazanin Tatari, Neil Savage, Sabra K. Salim, Chitra Venugopal, and Sheila K. Singh. "Advances in Immunotherapy for Adult Glioblastoma." Cancers 13, no. 14 (July 7, 2021): 3400. http://dx.doi.org/10.3390/cancers13143400.
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Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients.
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Polano, Maurizio, Marco Chierici, Michele Dal Bo, Davide Gentilini, Federica Di Cintio, Lorena Baboci, David L. Gibbs, Cesare Furlanello, and Giuseppe Toffoli. "A Pan-Cancer Approach to Predict Responsiveness to Immune Checkpoint Inhibitors by Machine Learning." Cancers 11, no. 10 (October 15, 2019): 1562. http://dx.doi.org/10.3390/cancers11101562.
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Immunotherapy by using immune checkpoint inhibitors (ICI) has dramatically improved the treatment options in various cancers, increasing survival rates for treated patients. Nevertheless, there are heterogeneous response rates to ICI among different cancer types, and even in the context of patients affected by a specific cancer. Thus, it becomes crucial to identify factors that predict the response to immunotherapeutic approaches. A comprehensive investigation of the mutational and immunological aspects of the tumor can be useful to obtain a robust prediction. By performing a pan-cancer analysis on gene expression data from the Cancer Genome Atlas (TCGA, 8055 cases and 29 cancer types), we set up and validated a machine learning approach to predict the potential for positive response to ICI. Support vector machines (SVM) and extreme gradient boosting (XGboost) models were developed with a 10×5-fold cross-validation schema on 80% of TCGA cases to predict ICI responsiveness defined by a score combining tumor mutational burden and TGF- β signaling. On the remaining 20% validation subset, our SVM model scored 0.88 accuracy and 0.27 Matthews Correlation Coefficient. The proposed machine learning approach could be useful to predict the putative response to ICI treatment by expression data of primary tumors.
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Golkaram, Mahdi, Chen Zhao, Kristina Kruglyak, Shile Zhang, and Sven Bilke. "The interplay between cancer type, panel size and tumor mutational burden threshold in patient selection for cancer immunotherapy." PLOS Computational Biology 16, no. 11 (November 9, 2020): e1008332. http://dx.doi.org/10.1371/journal.pcbi.1008332.
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The tumor mutational burden (TMB) is increasingly recognized as an emerging biomarker that predicts improved outcomes or response to immune checkpoint inhibitors in cancer. A multitude of technical and biological factors make it difficult to compare TMB values across platforms, histologies, and treatments. Here, we present a mechanistic model that explains the association between panel size, histology, and TMB threshold with panel performance and survival outcome and demonstrate the limitations of existing methods utilized to harmonize TMB across platforms.
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Chen, Krista Y., Aleksandra Popovic, David Hsiehchen, Marina Baretti, Paige Griffith, Ranjan Bista, Azarakhsh Baghdadi, et al. "Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors." Cancers 14, no. 21 (October 30, 2022): 5347. http://dx.doi.org/10.3390/cancers14215347.
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Background: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. Methods: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan–Meier statistics were used for progression-free survival (PFS) and overall survival (OS). Results: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/− cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3–4 immune related adverse events were observed in 4/19 (21.1%) patients. Conclusions: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.
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Miao, Diana, Claire Margolis, Dylan Martini, Stephanie Anne Mullane, Dana Cullen, Christine Horak, Megan Wind-Rotolo, et al. "Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 3016. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.3016.
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3016 Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) for ccRCC (N = 34) to discover genomic predictors of response to immune checkpoint therapy, and validated our findings in 28 ccRCC patients from 2 institutions treated with anti-PD-1 or anti-PD-L1 therapies. We defined 3 response groups: clinical benefit (CB) – complete or partial response by RECIST or stable disease with objective decrease in tumor burden and progression free survival (PFS) > 6 months - and no clinical benefit (NCB) – progressive disease with PFS < 3 months, with all other patients in intermediate benefit (IB). We further validated our findings in WES from 212 melanoma patients treated with immune checkpoint therapies in 3 published cohorts. Results: Biallelic loss of the chromatin remodeling subunit PBRM1, mutated in 34/62 (55%) patients across both cohorts and up to 41% of ccRCC overall, was the only gene mutation associated with CB in both the training (p = 0.0064; Pearson’s chi-squared) and validation cohorts (p = 0.043), and predicted both PFS and overall survival (OS) (p = 0.042 and 0.014, respectively; Kaplan-Meier). In 212 melanomas, truncating alterations in ARID2 – a closely related chromatin remodeler - were also enriched in responders after correcting for tumor mutational burden (p = 0.036), and having a truncating alteration in either PBRM1 or ARID2 significantly predicted overall survival (p = 0.022). In this ccRCC cohort, tumor mutational burden and loss of antigen presentation machinery were not associated with CB or NCB. Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy in both ccRCC and melanoma. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of ARID2 and PBRM1 in the context of the tumor-immune microenvironment will help to determine potential for further biomarker development.
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Vivaldi, Caterina, Silvia Catanese, Valentina Massa, Irene Pecora, Francesca Salani, Stefano Santi, Monica Lencioni, Enrico Vasile, Alfredo Falcone, and Lorenzo Fornaro. "Immune Checkpoint Inhibitors in Esophageal Cancers: Are We Finally Finding the Right Path in the Mist?" International Journal of Molecular Sciences 21, no. 5 (February 28, 2020): 1658. http://dx.doi.org/10.3390/ijms21051658.
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Esophageal cancer remains a challenging disease due to limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have been proven to be safe and effective in the treatment of highly lethal malignancies, such as non-small cell lung cancer and melanoma. Recent clinical trials also showed promising activity in immune checkpoint inhibitors in pretreated advanced esophageal carcinoma and a potentially significant impact on the outcome of selected patients, independently of histology. Combination studies evaluating immunotherapy and chemotherapy and, in localized disease, radiotherapy are in progress and will hopefully confirm their promises in the near future. However, reliable predictive biomarkers are still lacking. Indeed, at present, the role of programmed cell death ligand 1 expression and other factors (such as microsatellite instability and tumor mutational burden) as predictive biomarkers of benefit to immune checkpoint inhibitors is still controversial. Our aim was to explore the rationale of ICIs in esophageal cancer, review the results already available in multiple settings, and investigate future perspectives with single-agent and combination strategies.
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Shao, Yusra F., Yasmine Baca, Joanne Xiu, Ari M. Vanderwalde, Gino Kim In, Dave S. B. Hoon, Evidio Domingo-Musibay, et al. "Immune profiling of metastatic uveal melanoma and response to immune checkpoint inhibitors." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9565. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9565.
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9565 Background: Response to immune checkpoint inhibitors (ICI) in uveal melanoma (UM) is low. We aimed to elucidate tumor markers correlated with improved survival in ICI treated UM patients. Methods: Tumor samples of UM patients were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes assay or whole exome sequencing) and RNA (whole transcriptome sequencing). Somatic mutations were totaled to calculate tumor mutational burden (TMB) and cutoff for high vs low was 10 mt/MB. PDL1 was tested with immunohistochemistry for tumor staining and cutoff was ≥2+, 5% for high vs low. NCOA2 gene amplification was considered a surrogate for gain of chromosome 8q (cutoff ≥6). Median RNA expression level for LAG3 was calculated for each cohort and used as cutoff for high vs low. All ICI treated patients were considered to have metastatic disease. Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact. Time on treatment (TOT) was calculated from start to finish of ICI treatment and was considered as surrogate for progression-free survival (PFS). Comparison of survival was performed by Kaplan-Meier analysis. Results: A total of 450 UM samples were analyzed. Of these, 108 were from ICI treated patients and were obtained from primary (10/108) or metastatic (98/108) sites. Most tumors were PDL1 low in the entire UM (86%, 240/279) and ICI treated (62%, 55/89) cohorts. There was no difference in TOT between PDL1 high vs low in ICI treated cohort (HR 1.46, 95% CI 0.82-2.6, median TOT 3.1 months vs 2.3 months). Similarly, 98% (257/263) of all UM samples had low TMB. ICI treated patients with high LAG3 expression had similar TOT compared to low (HR 1.3, 95% CI 0.59-2.9, median TOT 6 months vs 2 months). In the entire UM cohort, most tumors were NF1-wildtype (95%, 56/59). NF1-wildtype status was associated with a longer rwOS compared to NF1-mutated (HR 0.18, 95% CI 0.051-0.64, median rwOS of 20.8 months vs 7 months). NCOA2 amplification was associated with a worse rwOS as compared to patients without NCOA2 amplification in the entire UM (HR 0.68, 95% CI 0.50-0.91) but not in ICI treated cohort (HR 0.84, 95% CI 0.52-1.4). There was no difference in TOT in ICI treated patients by BAP1 and SF3B1 mutational status. Conclusions: UM lacks traditional markers of response to ICI. Short TOT seen in our study is consistent with PFS of 3 to 5.5 months seen in clinical trials. High LAG3 expression was associated with a clinically significant improvement in TOT. Traditional markers of poor prognosis were not implicated in survival differences in ICI treated patients. This likely represents a poor prognosis in all mUM patients regardless of traditional prognostic markers. NF1 mutation is uncommon in UM and its significance as a prognostic marker should be validated in a larger cohort. Ongoing research is needed to understand the biology of UM and approach to treatment.
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Shao, Yusra F., Yasmine Baca, Joanne Xiu, Ari M. Vanderwalde, Gino Kim In, Dave S. B. Hoon, Evidio Domingo-Musibay, et al. "Immune profiling of metastatic uveal melanoma and response to immune checkpoint inhibitors." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9565. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9565.
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9565 Background: Response to immune checkpoint inhibitors (ICI) in uveal melanoma (UM) is low. We aimed to elucidate tumor markers correlated with improved survival in ICI treated UM patients. Methods: Tumor samples of UM patients were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes assay or whole exome sequencing) and RNA (whole transcriptome sequencing). Somatic mutations were totaled to calculate tumor mutational burden (TMB) and cutoff for high vs low was 10 mt/MB. PDL1 was tested with immunohistochemistry for tumor staining and cutoff was ≥2+, 5% for high vs low. NCOA2 gene amplification was considered a surrogate for gain of chromosome 8q (cutoff ≥6). Median RNA expression level for LAG3 was calculated for each cohort and used as cutoff for high vs low. All ICI treated patients were considered to have metastatic disease. Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact. Time on treatment (TOT) was calculated from start to finish of ICI treatment and was considered as surrogate for progression-free survival (PFS). Comparison of survival was performed by Kaplan-Meier analysis. Results: A total of 450 UM samples were analyzed. Of these, 108 were from ICI treated patients and were obtained from primary (10/108) or metastatic (98/108) sites. Most tumors were PDL1 low in the entire UM (86%, 240/279) and ICI treated (62%, 55/89) cohorts. There was no difference in TOT between PDL1 high vs low in ICI treated cohort (HR 1.46, 95% CI 0.82-2.6, median TOT 3.1 months vs 2.3 months). Similarly, 98% (257/263) of all UM samples had low TMB. ICI treated patients with high LAG3 expression had similar TOT compared to low (HR 1.3, 95% CI 0.59-2.9, median TOT 6 months vs 2 months). In the entire UM cohort, most tumors were NF1-wildtype (95%, 56/59). NF1-wildtype status was associated with a longer rwOS compared to NF1-mutated (HR 0.18, 95% CI 0.051-0.64, median rwOS of 20.8 months vs 7 months). NCOA2 amplification was associated with a worse rwOS as compared to patients without NCOA2 amplification in the entire UM (HR 0.68, 95% CI 0.50-0.91) but not in ICI treated cohort (HR 0.84, 95% CI 0.52-1.4). There was no difference in TOT in ICI treated patients by BAP1 and SF3B1 mutational status. Conclusions: UM lacks traditional markers of response to ICI. Short TOT seen in our study is consistent with PFS of 3 to 5.5 months seen in clinical trials. High LAG3 expression was associated with a clinically significant improvement in TOT. Traditional markers of poor prognosis were not implicated in survival differences in ICI treated patients. This likely represents a poor prognosis in all mUM patients regardless of traditional prognostic markers. NF1 mutation is uncommon in UM and its significance as a prognostic marker should be validated in a larger cohort. Ongoing research is needed to understand the biology of UM and approach to treatment.
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Wang, Shuangkuai, Yuantao Tong, Hui Zong, Xuewen Xu, M. James C. Crabbe, Ying Wang, and Xiaoyan Zhang. "Multi-Level Analysis and Identification of Tumor Mutational Burden Genes across Cancer Types." Genes 13, no. 2 (February 17, 2022): 365. http://dx.doi.org/10.3390/genes13020365.
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Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). However, there are still inconsistent standards of gene panels using next-generation sequencing and poor correlation between the TMB genes, immune cell infiltrating, and prognosis. We applied text-mining technology to construct specific TMB-associated gene panels cross various cancer types. As a case exploration, Pearson’s correlation between TMB genes and immune cell infiltrating was further analyzed in colorectal cancer. We then performed LASSO Cox regression to construct a prognosis predictive model and calculated the risk score of each sample for receiver operating characteristic (ROC) analysis. The results showed that the assessment of TMB gene panels performed well with fewer than 500 genes, highly mutated genes, and the inclusion of synonymous mutations and immune regulatory and drug-target genes. Moreover, the analysis of TMB differentially expressed genes (DEGs) suggested that JAKMIP1 was strongly correlated with the gene expression level of CD8+ T cell markers in colorectal cancer. Additionally, the prognosis predictive model based on 19 TMB DEGs reached AUCs of 0.836, 0.818, and 0.787 in 1-, 3-, and 5-year OS models, respectively (C-index: 0.810). In summary, the gene panel performed well and TMB DEGs showed great potential value in immune cell infiltration and in predicting survival.
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Ghidini, Michele, Angelica Petrillo, Andrea Botticelli, Dario Trapani, Alessandro Parisi, Anna La Salvia, Elham Sajjadi, Roberto Piciotti, Nicola Fusco, and Shelize Khakoo. "How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches." Journal of Clinical Medicine 10, no. 7 (April 1, 2021): 1412. http://dx.doi.org/10.3390/jcm10071412.
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Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.
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Li, Zhenxiang, Jiamao Lin, Lijuan Zhang, Jingchao Li, Yingyun Zhang, Chenglong Zhao, and Haiyong Wang. "Comprehensive analysis of multiple parameters associated with tumor immune microenvironment in ARID1A mutant cancers." Future Oncology 16, no. 29 (October 2020): 2295–306. http://dx.doi.org/10.2217/fon-2020-0243.
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Aim: To verify the relationship between ARID1A and tumor immune microenvironment thus immune checkpoint inhibitors (ICIs) response. Material & methods: Several public databases were used to characterize the association between ARID1A gene alteration and tumor immunity. Results: The gene mutation frequency was 8.2% in all cancer types. The ARID1A-mutated cancers have higher scores of mutation count, tumor mutational burden, neoantigen load (p < 0.001) and T cell repertoire, B cell repertoire diversity (p < 0.05). The gene mutation has tight association with multiple-activated immune cells. Survival analysis suggested that patients with ARID1A mutant cancers benefit more from ICIs treatment (p = 0.013). Conclusion: The ARID1A gene mutation was correlated with higher tumor immunogenicity and activated antitumor immune microenvironment, resulting in superior cohort that respond well to ICIs.
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Truong, Cao-Sang, and So Young Yoo. "Oncolytic Vaccinia Virus in Lung Cancer Vaccines." Vaccines 10, no. 2 (February 4, 2022): 240. http://dx.doi.org/10.3390/vaccines10020240.
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Therapeutic cancer vaccines represent a promising therapeutic modality via the induction of long-term immune response and reduction in adverse effects by specifically targeting tumor-associated antigens. Oncolytic virus, especially vaccinia virus (VV) is a promising cancer treatment option for effective cancer immunotherapy and thus can also be utilized in cancer vaccines. Non-small cell lung cancer (NSCLC) is likely to respond to immunotherapy, such as immune checkpoint inhibitors or cancer vaccines, since it has a high tumor mutational burden. In this review, we will summarize recent applications of VV in lung cancer treatment and discuss the potential and direction of VV-based therapeutic vaccines.
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Ngo, Carine, and Sophie Postel-Vinay. "Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments." Biomedicines 10, no. 3 (March 11, 2022): 650. http://dx.doi.org/10.3390/biomedicines10030650.
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Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid tumors (MRT), epithelioid sarcoma, poorly differentiated chordoma, and renal medullary carcinoma (RMC). Intriguingly, SMARCB1-deficient pediatric MRT and RMC have recently been reported to be immunogenic, despite their very simple genome and low tumor mutational burden. Responses to immune checkpoint inhibitors have further been reported in some SMARCB1-deficient diseases. Here, we will review the preclinical data and clinical data that suggest that immunotherapy, including immune checkpoint inhibitors, may represent a promising therapeutic strategy for SMARCB1-defective tumors. We notably discuss the heterogeneity that exists among the spectrum of malignancies driven by SMARCB1-loss, and highlight challenges that are at stake for developing a personalized immunotherapy for these tumors, notably using molecular profiling of the tumor and of its microenvironment.
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Kosari, Farhad, Maria Disselhorst, Jun Yin, Tobias Peikert, Julia Udell, Sarah Johnson, James Smadbeck, et al. "Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors." Journal of Thoracic Oncology 17, no. 3 (March 2022): 446–54. http://dx.doi.org/10.1016/j.jtho.2021.10.022.
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Ruiz de Porras, Vicenç, Juan Carlos Pardo, Lucia Notario, Olatz Etxaniz, and Albert Font. "Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?" International Journal of Molecular Sciences 22, no. 9 (April 29, 2021): 4712. http://dx.doi.org/10.3390/ijms22094712.
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Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.
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Nandakumar, Vijayalakshmi, and John R. Mills. "The Now and Beyond of Tumor Mutational Burden as a Predictor of Response to Immune Checkpoint Inhibitors." Clinical Chemistry 65, no. 2 (February 1, 2019): 357. http://dx.doi.org/10.1373/clinchem.2018.295097.
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Schrock, A. B., C. Ouyang, J. Sandhu, E. Sokol, D. Jin, J. S. Ross, V. A. Miller, et al. "Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer." Annals of Oncology 30, no. 7 (July 2019): 1096–103. http://dx.doi.org/10.1093/annonc/mdz134.
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Repáraz, David, Belén Aparicio, Diana Llopiz, Sandra Hervás-Stubbs, and Pablo Sarobe. "Therapeutic Vaccines against Hepatocellular Carcinoma in the Immune Checkpoint Inhibitor Era: Time for Neoantigens?" International Journal of Molecular Sciences 23, no. 4 (February 11, 2022): 2022. http://dx.doi.org/10.3390/ijms23042022.
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Immune checkpoint inhibitors (ICI) have been used as immunotherapy for hepatocellular carcinoma (HCC) with promising but still limited results. Identification of immune elements in the tumor microenvironment of individual HCC patients may help to understand the correlations of responses, as well as to design personalized therapies for non-responder patients. Immune-enhancing strategies, such as vaccination, would complement ICI in those individuals with poorly infiltrated tumors. The prominent role of responses against mutated tumor antigens (neoAgs) in ICI-based therapies suggests that boosting responses against these epitopes may specifically target tumor cells. In this review we summarize clinical vaccination trials carried out in HCC, the available information on potentially immunogenic neoAgs in HCC patients, and the most recent results of neoAg-based vaccines in other tumors. Despite the low/intermediate mutational burden observed in HCC, data obtained from neoAg-based vaccines in other tumors indicate that vaccines directed against these tumor-specific antigens would complement ICI in a subset of HCC patients.