Engineered CD4 TCR T cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer

Journal article

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

Authors: Saillard, M; Cenerenti, M; Reichenbach, P; Guillaume, P; Su, Z

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science Advances
• Volume: 11
• Issue: 26
• Pages: eadu5754-eadu5754
• Publication date: 2025-06-27
• DOI: 10.1126/sciadv.adu5754
• EISSN: 2375-2548
• ISSN: 2375-2548
• Language: English
• Keywords: Immunology; In vitro; CD8; Genetics; T-cell receptor; Cancer research; Medicine; Antigen; Immune system; Biology; Cytotoxic T cell; T cell; Immunotherapy; Interleukin 21; Adoptive cell transfer