Generation of Effective and Specific Human TCRs Against Tumor/testis Antigen NY-ESO-1 in Mice with Humanized T Cell Recognition System

Overview

Journal Front Immunol

Date 2025 Jan 8

PMID 39776913

Authors

Xiaojing Tina Chen

Matthias Leisegang

Ioannis Gavvovidis

Seth M Pollack

Felix K M Lorenz

Ton N Schumacher

Oliver Daumke

Thomas Blankenstein

Affiliations

Soon will be listed here.

Abstract

Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1 restricted to HLA-A*02:01. We compared the functions of the murine-derived TCR with human-derived TCRs and an affinity matured TCR, using co-culture and adoptive T cell transfer in tumor-bearing mice. Alanine scan, x-scan, LCL assay were employed to address the cross-reactivity of the NY-ESO-1 specific TCRs. We also used human tissue cDNA library and human primary cells to assess the safety of adoptive T cell therapies targeting NY-ESO-1 antigen in the clinic. One of the murine-derived human TCRs, TCR-ESO, exhibited higher functional avidity compared to human-derived NY-ESO-1 specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an affinity-matured TCR, TCR 1G4-α95LY, which was applied in clinical trials. TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-α95LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies.

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