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.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 75–85% of all liver cancers [1]
We have identified a number of T cell receptor (TCR) against AFP158−166 from HLA-A2 transgenic AAD mice with varied affinity using a lentivector-prime and peptide-boost approach [19]
The Epstein-Barr virus (EBV)–transformed B-lymphoblastoid cell lines (B-LCL) used for alloreactivity test were obtained from either Sigma or Fred Hutchinson Cancer Research Center, and maintained in RPMI 1640 medium supplemented with 15% fetal bovine serum (FBS) (VWR)
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 75–85% of all liver cancers [1]. T cell-based immunotherapy appears to be a promising clinical intervention for HCC patients due to the following observations. Efficacy of T cell-based immunotherapies against solid tumors, are still limited due to lack of optimal tumor specific targets, heterogeneity of tumor antigen expression, poor persistence of transferred cells, and immunosuppressive tumor microenvironment [7,8,9,10]. The safety profile remains good, and promising signs of clinical efficacy have been observed [17, 18], suggesting that AFP is a good target for T cell-based immunotherapies. We further confirmed that the selected TCR did not cross-react with the potential candidate with serials of validation assays Based on these analyses, we have selected a TCR based on the balance of its activity and safety profile. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated
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