He et al. developed a two-step screening method using antitumor immunity as a readout to identify preferred substitution position and substituted amino acids to generate enhanced TAA mimotopes (e-mimotopes) following immunization with a CPQ adjuvant system. E-mimotopes (Trp2-8C and 8Y) identified using the Trp2180–188 peptide showed improved Trp2-specific cytotoxic T cell phenotypes, TCR affinity (but not MHC-I affinity), antitumor immunity in prophylactic and therapeutic tumor models, and enhanced tumor control with ICB using anti- PD-1 and anti-CTLA-4 antibodies. The screening method also generated e-mimotopes for AH1 and WT1 epitopes.
Contributed by Shishir Pant
ABSTRACT: Tumor-associated self-antigens are potential cancer vaccine targets but suffer from limited immunogenicity. There are 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 identify such epitopes, which are referred to as enhanced mimotopes ("e-mimotopes"). Here, we present a generalized strategy to develop e-mimotopes, using the tyrosinase-related protein 2 (Trp2) peptide Trp2180-188, which is a murine major histocompatibility complex class I (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 antitumor 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 other murine MHC-I restriction elements, including epitopes within glycoprotein 70 and Wilms' Tumor Gene 1, to identify additional e-mimotopes with enhanced potency.
Author Info: (1) Biomedical Engineering, University at Buffalo, State University of New York. (2) Biomedical Engineering, University at Buffalo, State University of New York. (3) Biomedical Eng
Author Info: (1) Biomedical Engineering, University at Buffalo, State University of New York. (2) Biomedical Engineering, University at Buffalo, State University of New York. (3) Biomedical Engineering, University at Buffalo, State University of New York. (4) McGill University. (5) McGill University. (6) Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center. (7) Immunology, Roswell Park Comprehensive Cancer Center. (8) Biomedical Engineering, University at Buffalo, State University of New York jflovell@buffalo.edu.
