Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development  

作　　者：WEITAO ZHENG DONG JIANG SONGEN CHEN MEILING WU BAOQI YAN JIAHUI ZHAI YUNQIANG SHI BIN XIE XINGWANG XIE KANGHONG HU WENXUE MA 

机构地区：[1]Sino-German Biomedical Center,National“111”Center for Cellular Regulation and Molecular Pharmaceutics,Cooperative Innovation Center of Industrial Fermentation(Ministry of Education of China&Hubei Province),Hubei University of Technology,Wuhan,430068,China [2]Center of Research&Development,Beijing CorreGene Biotechnology Co.,Ltd.,Beijing,102206,China [3]Department of Medicine,Sanford Stem Cell Institute and Moores Cancer Center,University of California San Diego,La Jolla,CA 92093,USA

出　　处：《Oncology Research》2024年第12期1837-1850,共14页肿瘤学研究（英文）

基　　金：funded by the key R&D Project of Hubei Province(Social Development),China(2022BCA018);the Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),China(2022KF16)to Kanghong Hu.

摘　　要：Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.

关 键 词：T cell receptor(TCR) TCR therapy Tumor-infiltrating lymphocytes(TILs) Kirsten rat sarcoma virus(KRAS) G12D Alloreactivity 

分 类 号：R730.5[医药卫生—肿瘤]