Genomic correlates of response to CTLA-4 blockade in metastatic melanoma

By E. V. Van Allen, Diana Miao, B. Schilling, S. Shukla, C. Blank, L. Zimmer, A. Sucker, U. Hillen, M. G. Geukes Foppen, S. Goldinger and 12 more. Science, 2015

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Is cancer immunotherapy a private affair? Immune checkpoint blockade, a relatively new cancer treatment, substantially extends the survival of a subset of patients. Previous work has shown that patients whose tumors harbor the largest number of mutations—and thus produce a large number of “neoantigens” recognized as foreign by the immune system—are most likely to benefit. Expanding on these earlier studies, Van Allen et al. studied over 100 patients with melanoma and found a similar correlation (see the Perspective by Gubin and Schreiber). There was no evidence, however, that specific neoantigen sequences were shared by patients who responded. Science, this issue p. 207, see also p. 158 Melanoma patients who respond to immunotherapy do not appear to share common tumor neoantigens. [Also see Perspective by Gubin and Schreiber ] Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/20ace79f735dfa350fa6c5eb0fa431c68093b19a

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Citations in the corpus

Cancer immunotherapy: the beginning of the end of cancer? (2016, background): “For instance, according to two independent groups, the mutational frequency in melanoma tumors was correlated with clinical responses to anti-CTLA-4 therapy [156].”
Identification of essential genes for cancer immunotherapy (2017, methodology): “The analysis criteria were set as follows: (1) querying for molecules with Ingenuity Knowledge Base as a reference set; (2) restricted to human species; and (3) experimentally observed findings as a confidence level.”
Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance (2017, methodology): “An independent patient cohort shows copy number loss as a putative resistance mechanism To investigate the impact of higher burden of copy number loss on resistance in another cohort of patients on immune checkpoint blockade, we obtained WES SAM files from 110 melanoma patients and RNA sequencing (R”
Precision Cancer Medicine: Challenges and Opportunities (2019, methodology): “1975–1977: The first generation Sanger DNA sequencing method was invented [42, 43], which was further optimized and automated over the following decades [10, 12].”
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers (2017, result): “These results are consistent with those previously reported for ipilumumab in melanoma (32, 33).”
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade (2016, methodology): “For the subset of tumors where clonal analysis was possible (78/110 tumors, a smaller and less adequately powered cohort compared to the published analysis), total neoantigen burden was not significantly associated with efficacy of immune checkpoint inhibition [classified as in (17)], although a tre”