Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer.
Saillard M., Cenerenti M., Reichenbach P., Guillaume P., Su Z., Hafezi M., Schmidt J., Cesbron J., Genolet R., Queiroz L., Racle J., Villard J., Renella R., Michielin O., Zoete V., Rivals J-P., Irving M., Speiser DE., Harari A., Gfeller D., Adotevi O., Ceppi F., Coukos G., Romero P., Jandus C.
While cancer immunotherapy has primarily focused on CD8 T cells, CD4 T cells are increasingly recognized for their role in antitumor immunity. The HLA-DRB3*02:02 allele is found in 50% of Caucasians. In this study, we screened HLA-DRB3*02:02 patients with melanoma for tumor-specific CD4 T cells and identified robust New York esophageal squamous cell carcinoma 1 (NY-ESO-1)123-137/HLA-DRB3*02:02 CD4 T cell activity in both peripheral blood and tumor tissue. By analyzing NY-ESO-1123-137/HLA-DRB3*02:02-restricted CD4 T cell clones, we uncovered an unexpectedly high cytotoxicity, strong T helper 1 polarization, and recurrent αβ T cell receptor (TCRαβ) usage across patients and anatomical sites. These responses were also present in other NY-ESO-1-expressing cancers. TCRs from these clones, when transduced into primary CD4 T cells, showed direct antitumor efficacy both in vitro and in vivo. Our findings suggest that these TCRs are promising for adoptive T cell transfer therapy, enabling broader targeting of NY-ESO-1-expressing adult and pediatric cancers in clinical settings.