Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit

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

Research output: Contribution to journalArticle

Abstract

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. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). 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 a protein candidate identified by X-scan. At present we have selected an 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.

Original languageEnglish (US)
Article number623
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Apr 27 2020

Keywords

  • T cell receptor (TCR)
  • X-scan
  • alloreactivity
  • alpha-fetoprotein (AFP)
  • cross-reactivity
  • hepatocellular carcinoma (HCC)
  • immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Luo, X., Cui, H., Cai, L., Zhu, W., Yang, W. C., Patrick, M., Zhu, S., Huang, J., Yao, X., Yao, Y., He, Y., & Ji, Y. (2020). Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit. Frontiers in immunology, 11, [623]. https://doi.org/10.3389/fimmu.2020.00623