Abstract 1499: Targeting Ras mutation with TCR therapy

Abstract

Abstract Ras oncogenes (K/N/HRAS) are frequently mutated in 20% of all human cancers. Globally, approximately 3.4 million new cancer cases are diagnosed annually carrying Ras mutations. There is a large unmet medical need for treating cancers carrying Ras mutations. KRAS mutations account for around 80% of total Ras mutations. Codon 12 and 13 are most frequently mutated in KRAS oncogene. RasG12V and RasG13D represent approximately 22-58% cases of KRAS mutations. RAS mutations are immunogenic and can be recognized by T cell receptors in HLA restricted manner (Steven A. Rosenberg, 2016). Here we report identification of two human TCRs specifically recognizing RasG12V and RasG13D mutations isolated from tumor infiltrating lymphocytes of colorectal cancer patients. Both TCRs show high avidity to RasG12V and RasG13D mutations presented by MHCII alleles widely distributed in human population. Engineered B13.14.1 TCR-T and B8.2.4 TCR-T recognize RASG12V and RASG13D presented on HLA matched tumor cell line and induce strong INFγ release. Furthermore, potent yet specific tumor cell lysis was observed in multiple RASG12V and RASG13D tumor cell lines. Our RasG12V and RasG13D targeted TCR-T therapy could hold great potential for treatment of oncogenic Ras mutation driven cancers. Citation Format: Nan Mou, Yue Yu, Jijun Yuan. Targeting Ras mutation with TCR therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1499.