Abstract B002: A LIBRARY OF POTENT TCRS DERIVED FROM HEALTHY DONORS TARGETING KRAS G12D AND G12V NEOANTIGENS

Abstract Kirsten rat sarcoma (KRAS) is the most frequently altered oncogene, making mutant KRAS (mKRAS) an attractive target for neoantigen-specific T cell-based therapies. Identification of T cell receptors (TCRs) with strong and specific binding capabilities enables T cell therapies for cancer patients who harbor the respective mKRAS/HLA allele pair. Here, we generated the so far largest TCR warehouse library covering approximately one quarter of pancreatic ductal adenocarcinoma patients and 10% of colorectal cancer patients. There are eight TCRs in this library, targeting two KRAS G12D and six G12V neoantigens. The TCRs compare favorably based on expression, functional avidity, and cytotoxicity to existing clinical and literature benchmark TCRs. Warehouse TCRs are strong binders, exhibit robust cytotoxicity, and efficacy in in vivo models. Additionally, to evaluate potential safety risks, we performed cross-reactivity and alloreactivity analyses on two TCRs and did not observe any cross- or alloreactivities. Furthermore, detailed characterization of each TCR revealed unique biology for specific KRAS neoantigens. We show that TCRs recognize KRAS G12V on HLA-C*03:03 and HLA-C*03:04 interchangeably, thereby resulting in a single neoantigen with one of the highest frequencies. We observed a unique and striking enrichment in the gene segment, TRAV4*01, amongst 100 TCRs targeting G12V/C*03:03 and /C*03:04. Deeper analysis and understanding of these gene segments could be advantageous for future TCR discovery or optimization. Additionally, in the case of KRAS G12V/HLA-C*01:02, TCRs do not distinguish the mutant epitope from the wild-type epitope when exogenously loaded onto target cells, a phenomenon which has not been reported thus far. Our data suggests that in the natural processing and presentation setting, the level of wild-type epitope abundance appears to be significantly lower, creating a therapeutic window. In summary, an mKRAS-targeted TCR warehouse is introduced, comprising candidates for further preclinical and clinical development. Citation Format: Kendra Foley, Margaret Hallisey, Christian Yee, Tejashri Jadhav, Jared Dietze, Hannah Miller, Maria Massaro, Sebastian Newrzela, Marit van Buuren, Gavin Palowitch, Charles Dulberger, John Srouji, Richard Gaynor, Vikram Juneja. A LIBRARY OF POTENT TCRS DERIVED FROM HEALTHY DONORS TARGETING KRAS G12D AND G12V NEOANTIGENS [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B002.