Article
Author: Zhu, Daojun ; Yao, Anlong ; Shen, Rongxi ; Yu, Guangjie ; Qiu, Shuyi ; Wang, Sizhen ; Ouyang, Yonghao ; Jiang, Xiaochun ; Gan, Chi ; Li, Min ; Zhang, Xiaohui ; Wang, Xinbo ; Huang, Lei ; Wei, Ran ; Hu, Hong-Ming ; Sun, Zhufeng ; Chen, Yimin ; Chen, Ling ; Yang, Jiongming ; Wu, Dou ; Dai, Yanzhenzi ; Xiao, Yi
Purpose::To develop adoptive T-cell therapy with genetically engineered T-cell receptor (TCR; TCR-T) that recognizes the KRASG12V mutation, we performed an Investigational New Drug (IND)-enabling preclinical study of a new TCR (051). This TCR was isolated from a patient with pancreatic ductal adenocarcinoma with the KRASG12V mutation that could be presented by the HLA-A*11:01 allele, the most common allele of the Chinese population.
Experimental Design::In vitro experiments using T cells from healthy donors transduced with a retroviral vector expressing 051 TCR were performed to determine the TCR specificity and functionality. The tumor reactivity strictly depended on the expression of the G12V mutation and HLA-A*11:01 molecules. The alanine scan experiment did not detect potential “off-target” cross-reactivity against the human genome. Good Laboratory Practice studies were carried out to assess the antitumor efficacy, persistence, safety, and toxicities of adoptively transferred human 051 TCR-T cells (IX001) in immunodeficient mice bearing human pancreatic cancer xenografts.
Results::After T-cell infusion, a potent antitumor effect was observed with or without IL-2 administration. The analysis of TCR gene integration in host T cells by retrovirus indicated a low risk of developing secondary malignancy. There was no evidence of TCR-T–related toxicity and genotoxicity induced by the retroviral vector.
Conclusions::IX001 was safe and highly efficacious in a pancreatic cancer CDX model. Our data support further clinical development of IX001 for HLA-A*11:01 patients with the KRASG12V mutation.