Tuning T cell receptor affinity to optimize clinical risk‐benefit when targeting α‐fetoprotein‐positive liver cancer

Abstract

Patients with hepatocellular carcinoma (HCC) have a poor prognosis and limited therapeutic options. α‐Fetoprotein (AFP) is often expressed at high levels in HCC and is an established clinical biomarker of the disease. Expression of AFP in non‐malignant liver can occur, particularly in a subset of progenitor cells and during chronic inflammation, at levels typically lower than in HCC. This cancer‐specific overexpression indicates AFP may be a promising target for immunotherapy. We verified the expression of AFP in normal and diseased tissue and generated an affinity optimized T cell receptor (TCR) with specificity to AFP/HLA‐A*02⁺ tumors. Expression of AFP was investigated using database searches, by qPCR, and by immunohistochemical analysis of a panel of human tissue samples, including normal, diseased and malignant liver. Using in vitro mutagenesis and screening, we generated a TCR that recognizes the HLA‐A*02‐restricted AFP_158‐166 peptide FMNKFIYEI with an optimum balance of potency and specificity. These properties were confirmed by an extension of the alanine scan (X‐scan) and testing TCR transduced T cells against normal and tumor cells covering a variety of tissues, cell types, and HLA alleles. Conclusion: We have used a combination of physicochemical, in silico, and cell biology methods for optimizing a TCR for improved affinity and function, with properties that are expected to allow TCR‐transduced T cells to differentiate between antigen levels on non‐malignant and cancer cells. T cells transduced with this TCR constitute the basis for a first‐in‐human trial of HCC adoptive T cell immunotherapy.

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