Abstract 1762: InhibigensTM subvert otherwise-efficacious cancer vaccines and immunotherapies in conjunction with alterations in the tumor microenvironment

Abstract

Abstract The current study explores the mechanism of Inhibigens: a new class of immune-dampening cancer neoantigens. Inhibigens are identified through Genocea's ATLASTM platform, an empirical and unbiased bioassay that utilizes autologous patient cells to characterize tumor mutations that elicit anti-tumor CD4+ and CD8+ immune responses. Unexpectedly, ATLAS also identifies inhibitory neoantigens (Inhibigens) that lead to downregulation of T cell inflammatory cytokine secretion. Previous studies demonstrated that when a single ATLAS-identified Inhibigen was administered to B16F10 tumor-bearing mice, it completely abrogated immunogenicity and efficacy of a protective vaccine. Thus, it is critical that detrimental Inhibigens be excluded from targeted immunotherapies and further studied to understand their global importance in cancer. Here we report progress in uncovering mechanisms of Inhibigen function. In ATLAS screening assays, patient-derived antigen-presenting cells (APCs) are fed with E. coli bacteria expressing individual mutations from the patient's mutanome with or without pore-forming listeriolysin O (cLLO), and subsequently exposed to patient-derived CD8+ or CD4+ T cells, respectively; T cell cytokine secretion determines antigen-specific responses. Unlike in silico approaches, ATLAS accounts for the complexity of antigen processing, the diversity of MHC class I and II alleles across races and ethnicities, and the diversity of T cell repertoires across individuals. ATLAS screening of B16F10 mouse melanoma previously identified stimulatory neoantigens and Inhibigens that were either protective or deleterious to tumor progression when included in vaccines, respectively. Current studies explore the tumor microenvironment (TME) and systemic immunity in Inhibigen-administered mice ± checkpoint inhibitors (CPI). Inhibigens accelerated tumor growth compared to protective vaccines, abrogated vaccine-driven infiltration of T cells and myeloid cells into the TME, and impaired the synergistic effects of vaccination and CPI therapy with corresponding deficiencies in the TME. In vitro studies thus far exclude cell killing and MHC competition as Inhibigen mechanisms of action. Ongoing studies evaluating Inhibigen modulation of APC and T cell function in vitro and in vivo will be presented. Our data enforce the necessity of identifying Inhibigens empirically and excluding them from cancer vaccines and immunotherapies. Genocea's GEN-009 and GEN-011 phase 1/2 clinical trials utilize ATLAS to identify optimal neoantigens and omit Inhibigens from cancer vaccines and T cell therapies. Ongoing exploration of Inhibigen phenotypes and mechanisms will illuminate new paradigms of cancer immunology and potentially pave the way for novel cancer immunotherapies. Citation Format: Hanna Starobinets, Victoria L. Devault, Stephanie Rinaldi, Julie Arnold, Osaruese Odeh, Cindy Nguyen, Jessica B. Flechtner, Hubert Lam. InhibigensTM subvert otherwise-efficacious cancer vaccines and immunotherapies in conjunction with alterations in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1762.