Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158-166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit.

Methods: To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs on balance of their potency and specificity by testing their reactivity to normal and transformed cells covering a variety of primary cell types and HLA serotypes, and potential protein candidate in human genome by an extensive alanine scan (X-scan).

Results: We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with protein candidate in human genome identified by X-scan.

Conclusion: Up to date we have selected a AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.

Citation Format: Xiaobing Luo, Huijuan Cui, Lun Cai, Wei Zhu, Wei-Chih Yang, Michael Patrick, Shigui Zhu, Jiaqi Huang, Xin Yao, Yihong Yao, Yukai He, Yun Ji. Selecting clinical lead of TCRs targeting alpha-fetoprotein-positive liver cancer on balance of risk and benefit [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6589.