Abstract 2065: A small molecule approach to drive novel neoantigen generation: First-in-class inhibitors of ERAP1 generate novel neoantigens driving anti-tumor effects

Abstract Immune checkpoint inhibition (ICI) therapy has changed the cancer treatment paradigm; however, most patients respond poorly to ICI alone. In order to be effective, ICI requires neoantigen expression to drive anti-tumor T cell responses and numerous clinical studies have shown that high neoantigen load and tumor mutation burden correlate with improved patient response. Given the central importance of neoantigens in ICI response there is an urgent need for therapies that generate new neoantigens to drive novel anti-tumour cytotoxic T cell responses thereby increasing the number of patients achieving durable benefit. Grey Wolf are developing inhibitors of endoplasmic reticulum aminopeptidases (ERAP1 and ERAP2) to generate novel neoantigens. ERAP enzymes are members of the antigen presentation pathway, trimming a subset of peptides (15-20%) prior to their loading onto MHC Class I. Strikingly, reduced tumoral expression of ERAP1 in cancer correlates with a 50% increase in overall survival. Independent groups have also shown that ablation of ERAP1 generates neoantigens, causing tumor growth inhibition in various syngeneic models in combination with ICI. Grey Wolf have generated and profiled highly potent and selective ERAP1 inhibitors, leading to the nomination of the first-in-class ERAP1 inhibitor development candidate, GRWD5769. Extensive analysis of the immunopeptidomes of diverse cancer cell lines robustly show that ERAP1 inhibition consistently generates novel neoantigens in vitro and in vivo. Analysis of syngeneic tumor models treated with an orally administered ERAP1 inhibitor in combination with anti-PD-1 show that neoantigen generation produces a differentiated T cell response, including: 1) diversification of the tumoral T cell repertoire; 2) increased infiltration of T cells into tumors; and 3) synergistic upregulation of translationally relevant immune gene markers shown to correlate with response to anti-PD-1 in patients. In addition, elevations in immune mediated effects caused by ERAP1 inhibition in combination with anti-PD-1 correlate with tumor growth inhibition in mouse syngeneic studies. Importantly, ERAP1 inhibitors are well tolerated in mouse, rat, and non-human primates, which aligns with the observations that increases in T cell effects are tumor specific and not observed in peripheral tissue. Our investigation of the effects of ERAP1 inhibitors in mouse tumor models and ex vivo primary human T cell co-cultures have provided proof of mechanism and proof of principle biomarkers that will be used to explore the effects of GRWD5769 during Phase 1 clinical development in the second half of 2022. Citation Format: Andrew Leishman, Wayne Paes, Richard Coulson, Michael Pinggera, Jessica Sette, Kate Anderton, Nicola Ternette, Juliet Morgan, Jason Shiers, Martin Quibell, Peter Ian Joyce. A small molecule approach to drive novel neoantigen generation: First-in-class inhibitors of ERAP1 generate novel neoantigens driving anti-tumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2065.