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Abstract 3182: Directed screening TCRs against Ras mutations in mCRC patients

Ras gene is involved in many signaling pathway to regulate cell proliferation, metabolism and motility, for example MAPK and PI3K pathway. Ras mutation is constitutively active to drive uncontrolled cell proliferation that results in malignant transformation. Ras mutation frequently occurs in human malignancy, for example pancreatic cancer (98%), colorectal cancer (45%) and lung cancer (31%). Drug development targeting Ras mutation was not succeed despites decades of effort in small molecule fields. T cell receptor (TCRs) can recognize processed and presented neoantigens on human leukocytes antigen (HLA). Ras G12D mutation was report as neoantigen and could be recognized by tumor infiltrating lymphocytes restricted by HLA-C0802 in mCRC patients. We assume that human TCR repertoire encompassing specific TCRs against Ras mutation restricted by other HLAs in Chinese patients. We design a novel synthetic presentation mRNA construct which harboring all pathogenic Ras mutations. The construct significantly enhanced Ras mutation peptides presentation on HLAs (>60%) compared with conventional used construct. We developed a directed screening method to identify T cell clone against Ras mutation restricted by Chinese pop HLAs in tumor infiltrating lymphocytes and sequenced TCRs by using 10xGenomics. We identified several TCRs that showed effector function against Ras mutation in China mCRC patients for further developing TCR-T cell therapy. Citation Format: Jijun Yuan. Directed screening TCRs against Ras mutations in mCRC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3182.