Abstract 4161: An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity

Abstract

Abstract Tumor-associated self-antigens are cancer vaccines targets but suffer from limited immunogenicity. There have been examples of mutated, short self-peptides inducing epitope-specific CD8+ T cells more efficiently than the wild-type epitope, but current approaches cannot yet reliably generate such enhanced mimotopes (“e-mimotopes”). Here, we present a generalized strategy to develop e-mimotopes, using the tyrosinase-related protein 2 peptide Trp2180-188, a major histocompatibility complex (MHC)-I epitope, as a test case. Using a vaccine adjuvant that induces peptide particle formation and strong cellular responses with nanogram antigen doses, a two-step method systematically identified e-mimotope candidates with murine immunization. First, position-scanning peptide micro libraries were generated in which each position of the wild-type epitope sequence was randomized. Randomization of only one specific residue of the Trp2 epitope increased anti-tumor immunogenicity. Second, all 20 amino acids were individually substituted and tested at that position, enabling the identification of two e-mimotopes with single amino acid mutations. Despite similar MHC-I affinity compared to the wild-type epitope, e-mimotope immunization elicited improved Trp2-specific cytotoxic T cell phenotypes and improved T cell receptor affinity for both the e-mimotopes and the native epitope, resulting in better outcomes in multiple prophylactic and therapeutic tumor models. The screening method was also applied to other targets with different murine MHC-I restriction elements, including the gp70 AH1 epitope, to identify additional e-mimotopes with enhanced potency. Citation Format: Xuedan He. An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity [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 4161.