Abstract 4112: Identification of Th1-specific epitopes from non-mutated KRAS lesions for off-the-shelf cancer vaccines

Abstract

Abstract Background KRAS is crucial for cell growth, differentiation, and signaling. Mutations in the KRAS gene (i.e., codon 12 or 13) are frequently associated with the development and progression of cancer, particularly lung, colorectal, and pancreatic cancers. Recently, it has been captured that KRAS targeting cancer vaccine research and clinical trials have been conducted in certain tumor types and vaccine approaches are encouraged to move forward. It has been well known that the tumor-eradicating efficacy of cancer vaccines arises from Th1 epitope selection. While tumor growth may persist after immunization with non-selected epitopes (including full-length), immunization with a highly selected Th1-specific epitope vaccine can lead to tumor regression by suppressing the activation of immune inhibitory cells. The Th-Vac® discovery platform uses a combination of in-silico, in-vitro, and in-vivo studies to precisely identify Th1-specific epitopes. It consists of two modules: module 1 (in-silico) and module 2 (in-vitro and efficacy evaluation). The aim is to identify MHC class II epitopes that are specific to antigens for CD4+ T cells, displaying the most favorable binding affinity across diverse alleles. Th1-specific epitope vaccines aim to boost and sustain T cell immunity against tumor antigens, overcoming the lack of a precise T cell response or pre-existing tolerance in the immunosuppressive TME. This study aimed to explore Th1-specific epitopes for KRAS vaccine to be potentially effective in numerous KRAS mutation-driven cancers. Methods Peptide sequence candidates that have highly potential of MHC class II binding affinity were comprehensively predicted via a module 1 (ASEP program). All of peptides selected in ASEP were synthesized as 15 mers. Each peptide was evaluated for immunogenicity using ELISpot and/or FACS analysis in module 2 (2a for in vitro and 2b for in vivo immunologic evaluation) of the Th-Vac® discovery platform. Specifically, in Module 2b, immunogenicity was evaluated using a 38-mer peptide formed by combining five overlapping peptides selected in 2a. These kinds of immunogenicity evaluations were conducted using type 1 and/or type 2 cytokine(s) produced by CD4+ T cells. Results In ASEP prediction, twelve peptides were selected as potential candidates demonstrating a high affinity to MHC class II, which were in different lesions of common mutation of KRAS. In module 2 using ELISpot and FACS analysis, two epitopes (non-mutated sequences) were finally selected as Th1-specific epitopes based on the type 1 T cell response. Conclusion Unlike previous vaccines using mutant lesions, in this study, two non-mutated Th1-specific epitopes are under the in-vivo efficacy studies as mono and combining regimen(s) in certain tumor types. Additionally, the Th-Vac® platform was fully validated in terms of the performance and its application would be expanded beyond a cancer vaccine. Citation Format: Youngki Choi, Jinback Lim, Hyo-Hyun Park, Jinho Kang, Hun Jung. Identification of Th1-specific epitopes from non-mutated KRAS lesions for off-the-shelf cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4112.