Zhang and Rohweder et al. demonstrated that drug-induced covalent modifications on tumor-specific somatic mutations formed functional MHC class I complexes, which could be exploited for immunotargeting. Investigational K-RasG12C inhibitor (ARS1620)-generated modified peptides formed functional MHC class I complexes with HLA-A*02:01 and HLA-A*03:01 and presented haptanated peptides on mutant on K-RasG12C cells. A bispecific T cell engager generated to recognize K-Ras(G12C)-derived peptide neoantigens elicited a cytotoxic T cell response against KRASG12C cells, including those resistant to direct KRAS G12C inhibition in vitro.
Contributed by Shishir Pant
ABSTRACT: Immunotargeting of tumor-specific antigens is a powerful therapeutic strategy. Immunotherapies directed at MHC-I complexes have expanded the scope of antigens and enabled the direct targeting of intracellular oncoproteins at the cell surface. We asked whether covalent drugs that alkylate mutated residues on oncoproteins could act as haptens to generate unique MHC-I-restricted neoantigens. Here, we report that KRAS G12C mutant cells treated with the covalent inhibitor ARS1620 present ARS1620-modified peptides in MHC-I complexes. Using ARS1620-specific antibodies identified by phage display, we show that these haptenated MHC-I complexes can serve as tumor-specific neoantigens and that a bispecific T cell engager construct based on a hapten-specific antibody elicits a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition. With multiple K-RAS G12C inhibitors in clinical use or undergoing clinical trials, our results present a strategy to enhance their efficacy and overcome the rapidly arising tumor resistance.