Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer
- Margaux Saillard
- Mara Cenerenti
- Patrick Reichenbach
- Philippe Guillaume
- Ziyang Su
- Morteza Hafezi
- Julien Schmidt
- Julien Cesbron
- Raphaël Genolet
- Lise Queiroz
- Julien Racle
- Jean Villard
- Raffaele Renella
- Olivier Michielin
- Vincent Zoete
- Jean-Paul Rivals
- Melita Irving
- Daniel E. Speiser
- Alexandre Harari
- David Gfeller
- Olivier Adotevi
- Francesco Ceppi
- George Coukos
- Pedro Romero
- Camilla Jandus
2025-07-25
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-1 123–137 / 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.