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Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell
Xiaojing Tina Chen1,2, Matthias Leisegang3,4, Ioannis Gavvovidis1,2
1Molecular Immunology and Gene Therapy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
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-1157-165 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 in vitro co-culture and in vivo 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-1157-165 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-1157-165 specific TCRs. TCR-ESO appeared to have similar efficiency in antigen recognition as an in vitro 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.
Insights
Generating T cell receptors (TCRs) for cancer therapy is challenging due to natural tolerance. Transgenic mice yielded TCR-ESO, a potent and specific TCR against the NY-ESO-1 antigen, offering a promising tool for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immune tolerance mechanisms hinder the generation of high-avidity T cell receptors (TCRs) crucial for effective cancer immunotherapy.
- The NY-ESO-1 antigen, a cancer-testis antigen, is a promising target for T cell therapies due to its widespread expression in various cancers and limited presence in normal tissues.
Purpose of the Study:
- To isolate and characterize novel, high-avidity TCRs targeting the NY-ESO-1 antigen using a transgenic mouse model.
- To compare the functional avidity, specificity, and safety of a murine-derived TCR (TCR-ESO) against human-derived TCRs and an affinity-matured TCR (1G4-α95LY) for adoptive T cell therapy.
Main Methods:
- Isolation of NY-ESO-1-specific TCRs from transgenic mice with a human TCR repertoire.
- Functional comparison using in vitro co-culture and in vivo adoptive T cell transfer models in tumor-bearing mice.
- Assessment of TCR cross-reactivity via alanine scan, x-scan, and LCL assays, and safety evaluation using human tissue cDNA libraries and primary cells.
Main Results:
- A murine-derived human TCR, TCR-ESO, demonstrated higher functional avidity than human-derived TCRs against NY-ESO-1.
- TCR-ESO exhibited comparable antigen recognition efficiency to the clinically applied affinity-matured TCR 1G4-α95LY but with significantly reduced cross-reactivity.
- Safety assessments indicated minimal cross-reactivity for TCR-ESO, suggesting potential clinical utility.
Conclusions:
- Human tolerance mechanisms likely eliminate highly effective NY-ESO-1-specific TCRs, posing a barrier to their therapeutic use.
- TCR gene loci transgenic mice serve as a valuable resource for isolating potent and specific TCRs for adoptive T cell therapies against cancer.
- TCR-ESO represents a promising candidate for developing safer and more effective cancer immunotherapies targeting NY-ESO-1.
