Influence Of Tumor Mutation Burden On Response To Anti-Pd-1 Treatment In Murine Models Of Melanoma

Therapeutic antibodies directed against immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), have recently shown remarkable clinical benefits, particularly in metastatic melanoma and non-small cell lung cancer (NSCLC), cancers largely caused by chronic exposure to mutagenic agents. Recent studies have focused on identifying genomic and immune predictors of response, but consistent, robust biomarkers have yet to be fully characterized. However, some data suggests a high non-synonymous tumour mutation burden is associated with clinical benefit in melanoma patients who received anti-CTLA-4 therapy. A similar correlation was also found in NSCLC patients treated with anti-PD-1. Using mouse models of BRAFV600E-driven melanoma, we examined the relationship between tumour mutation burden and response to the immune checkpoint inhibitor anti-PD-1. Chronic exposure to ultraviolet radiation (UVR) was used to increase the number of tumour non-synonymous single nucleotide variants (SNVs), and thus mutational load. Responses to PD-1 blockade were compared between tumours having low (∼10 SNVs) and high (u003e100 SNVs) mutation burden and tumours were subsequently subjected to comprehensive molecular and immune profiling using whole exome sequencing, immunohistochemistry, and flow cytometry. Our initial data suggest there is no significant correlation between tumour mutation burden and response in our model of BRAFV600E-driven melanoma, and we will present a detailed analysis of low- and high-mutation burden tumours in light of their response to PD-1 blockade. Consistent with previous studies, our results highlight that integrated molecular characterization of tumour tissue and associated microenvironment in larger cohorts is needed to identify robust determinants of response to immune checkpoint inhibitors. Citation Format: Elena Galvani, Kate Hogan, Gabriela Gremel, Amaya Viros, Amit K. Mandal, Matthew Smith, Jacqueline Swan, Antonia Banyard, Garry Ashton, Nathalie Dhomen, Richard Marais. Influence of tumor mutation burden on response to anti-PD-1 treatment in murine models of melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3207.