Abstract A168: T cell receptor-based bispecific molecules targeting KRAS neoantigen cancer driver mutations

Abstract

KRAS is the most frequently mutated oncogene. Tumour specific neoantigen peptides derived from KRAS are presented by cell surface human leucocyte antigens (HLA) and form a class of shared, public tumour-specific antigens for T cell receptors (TCR) that are attractive targets for immunotherapy. We have previously reported engineering of a soluble T cell engaging ImmTAC (Immune mobilising monoclonal TCR Against Cancer) molecule, IMC-KRASG12D specific for KRASG12D peptide presented by HLA-A*11:01. IMC-KRASG12D was extensively characterised and demonstrated potent redirection of T cell cytotoxicity towards target KRASG12D presenting cancer cells, while sparing normal cells. Here, we focus on TCRs isolated from healthy donors that specifically recognise KRASG12V peptides presented in the context of HLA-A*11:01 or HLA-A*03:01. The affinity of several TCRs was enhanced by phage display, retaining the remarkable ability to distinguish between KRASG12V and KRASWT peptides. In cell-based assays, ImmTAC molecules containing these TCR mediate T cell activation in response to cells expressing KRASG12V but not KRASWT. Interestingly, although structural, biochemical, and computational approaches can explain the molecular mechanism underlying TCR selectivity for KRASG12D pHLA-A*11complexes, it remains unclear how TCR selectivity to KRASG12V is achieved. These studies demonstrate that affinity enhanced TCR can maintain selectivity for target peptides that differ from self-antigens by only a single amino acid, to enable targeting of public neoantigens.

Citation Format: Andrew D Whale, Milos Aleksic, Vijaykumar Karuppiah, Sylvie Moureau, Chandramouli Chillakuri. T cell receptor-based bispecific molecules targeting KRAS neoantigen cancer driver mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A168.