Clinical data demonstrates increased antigen presentation diversity is an important factor in determining response rates to checkpoint inhibitors. In addition to tumor mutational burden, increased HLA heterozygosity and HLA evolutionary diversity are non-overlapping factors which further diversify the immunopeptidome and improve clinical response to checkpoint therapies. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides loaded into classical and nonclassical MHC Class I molecules. Human genome-wide association studies have identified single nucleotide polymorphisms within ERAP1 that are associated with immune-related diseases, such as ankylosing spondylitis, providing human genetic validation for ERAP1's role in human disease and antigen presentation. Further, ablation of mouse ERAAP modifies the immunopeptidome, resulting in improved immunogenicity, generation of CD8+ T cell responses and tumor growth inhibition.

Grey Wolf Therapeutics have developed highly potent and selective ERAP1 inhibitors. These inhibitors demonstrate significant modulation of the cancer-related antigen repertoire across diverse ERAP1 and HLA genotypes and cancer-type backgrounds, both in vitro and in vivo. These changes in the antigen repertoire drive changes in T cell activation and response, leading to increased T cell infiltration into CT26 syngeneic tumors and T cell receptor (TCR) diversification when combined with anti-PD-1. We have identified immune related markers that are modulated following ERAP1 inhibition in syngeneic tumor models which have the potential to be used as biomarkers. Importantly, ERAP1 inhibitor induced immunopeptidome and T cell changes lead to significant tumor growth inhibition in syngeneic mouse models when combined with anti-PD-1. In parallel, we have demonstrated the ability of ERAP1 inhibitor induced novel cancer associated antigens to stimulate human CD8+ T cell responses. Extensive assessment of the potential of ERAP1 inhibitors to enhance tumor immune responses in combination with additional therapies (e.g. chemotherapy and radiotherapy), across different tumor microenvironments, is ongoing. These data provide the foundation from which we plan to explore the potential of our first-in-class ERAP1 inhibitor development candidate in the clinic.

Citation Format: Andrew Leishman, Fergus Poynton, Nicola Ternette, Elisa Lori, Camila de Almeida, Henry Leonard, Emma Reeves, Edd James, Kristopher Clark, Carmen Tong, Jason Shiers, Martin Quibell, Peter Ian Joyce. First in class inhibitors of ERAP1 have the potential to be a transformative immunotherapy in oncology [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 1715.