Abstract 3467: GRWD5769: A first-in-class inhibitor of ERAP1, generating novel cancer antigens to drive de novo anti-tumor T cell responses

Abstract Immune checkpoint inhibitors (ICI) have changed the cancer treatment paradigm, yet significant unmet need remains. Clinical data shows that increasing antigen presentation diversity, genomic instability, tumor mutational burden and HLA diversity, as well as preventing permanent exhaustion of pre-existing cytotoxic T cells, caused by chronic cancer antigen stimulation, are all factors that improve clinical response to ICI. Additionally, increasing presentation of cancer-specific target peptides on cancer cells will enhance T cell receptor (TCR)-mediated therapeutics such as ImmTACs or TCR-Engineered T cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims peptides loaded into classical and non-classical MHC Class I. In cancer, knockout or inhibition of ERAP1 changes a proportion of the antigen repertoire, generating and upregulating cancer antigens. This leads to the activation of de novo anti-tumor T cell responses, causing tumor growth inhibition and bypassing T cell exhaustion. We report the preclinical development, characterization and mechanistic analysis of the first-in-class ERAP1 inhibitor, GRWD5769. Extensive analysis of the immunopeptidomes of diverse cancer cell lines robustly showed that GRWD5769 modulates the cancer-related antigen repertoire across genotypes and cancer-type backgrounds. Novel or upregulated neoantigens generated by ERAP1 inhibition are conserved across cancer cell types and genetic backgrounds. ERAP1 inhibition in combination with an ICI (anti-PD1 mAb) diversified the TCR repertoire, upregulated prognostic immune gene markers in the tumor, including markers for recently activated (thus non-exhausted) T cells, and drove infiltration of T cells into syngeneic mouse model tumors. This combination is efficacious across syngeneic models, including different mouse strains and the effects of ERAP1 inhibition on the T cell response correlate with efficacy. Further, ex vivo human T cell co-cultures with cancer cell lines demonstrate that novel and upregulated neoantigens generated by ERAP1 inhibition drive tumor cell killing. In addition, these studies showed enhanced tumor cell killing when an ImmTAC was used in combination with ERAP1 inhibition to enhance presentation of the cancer-specific target peptide. In conclusion, the first-in-class, ERAP1 inhibitor clinical candidate, GRWD5769, drives novel anti-tumor T cell responses through neoantigen creation and circumventing T cell exhaustion. GRWD5769 has demonstrated a good safety profile in GLP toxicology studies and robust proof of mechanism and proof of principle biomarkers have been developed to provide a clear path to establish the activity and efficacy of GRWD5769 in patients in 2023. Citation Format: Andrew Leishman, Wayne Paes, Emma Sparrow, Ana Ribeiro, Michael Cundell, Milos Aleksic, Michael P. Pinggera, Jessica Sette, Kate Anderton, Nicola Ternette, Juliet Morgan, Jason J. Shiers, Martin Quibell, Peter I. Joyce. GRWD5769: A first-in-class inhibitor of ERAP1, generating novel cancer antigens to drive de novo anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3467.