Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity

Abstract

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize scFvs against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V or G12D mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs.

Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma

“…Most recently, pan- KRAS inhibitor RMC-6236, which binds to the chaperone protein cyclophilin A and active GTP-bound RAS (RAS ON inhibitor), is also being tested in patients (NCT05379985). Finally, T cell therapy with KRAS G12D -targeting T cell receptors (TCRs) caused tumor regression in a patient with pancreatic cancer, and T cells with TCRs targeting other KRAS mutations, such KRAS G12V , are under development 22 , 23 .…”

Impact of KRAS Mutations and Co-mutations on Clinical Outcome in Pancreatic Ductal Adenocarcinoma

“…Pan KRAS inhibitor RMC-6236, which binds to the chaperone protein, cyclophilin A, and active GTP-bound RAS (RAS ON inhibitor) are also being tested in patients with KRAS G12 mutations, including G12D, G12V, G12R, G12A, or G12S mutations ( NCT05379985 ). Moreover, T cell therapy with KRAS G12D -targeting T cell receptors (TCRs) caused tumor regression in a pancreatic cancer patient, and T cells with TCRs targeting other KRAS mutations, such KRAS G12V , are under development 22 , 23 . We are at a breakthrough point in attempts to target KRAS in pancreatic cancer.…”