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

Q: How did the study identify NY-ESO-1–specific CD4 T cells?

Researchers screened HLA-DRB3*02:02 melanoma patients to find robust tumor-specific CD4 T cells and then analyzed NY-ESO-1(123–137)/HLA-DRB3*02:02–restricted CD4 T cell clones from blood and tumor tissue.

Sep 23, 2026

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Cancer immunotherapy increasingly recognizes CD4 T cells as important antitumor effectors alongside CD8 T cells. This study screened HLA-DRB3*02:02 patients with melanoma and identified strong NY-ESO-1(123–137)/HLA-DRB3*02:02 CD4 T cell activity in peripheral blood and tumor tissue. Clone analysis revealed unexpectedly high cytotoxicity, pronounced Th1 polarization, and recurrent αβ TCR usage across patients and anatomical sites. TCRs transduced into primary CD4 T cells showed direct in vitro and in vivo antitumor efficacy, supporting adoptive transfer targeting NY-ESO-1–expressing adult and pediatric cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Rationale for CD4 T cells in cancer immunotherapy

Adoptive T cell transfer and limitations of CD8-only targeting

Challenges for CD4 T cell therapies (HLA/MHC polymorphism)

NY-ESO-1 as a therapeutic target

CANCER Engineered CD4 TCRT cells with conserved high-affinity TCRs targeting NY-ESO-1 for advanced cellular therapies in cancer Margaux Saillard1,2,3,4,5, Mara Cenerenti2,3,4,5, Patrick Reichenbach1,2, Philippe Guillaume1,2, Ziyang Su2,3,4,5, Morteza Hafezi1,2, Julien Schmidt1,2, Julien Cesbron1,2, Raphaël Genolet1,2, Lise Queiroz1,2, Julien Racle1,2,6, Jean Villard7,8, Raffaele Renella9, Olivier Michielin10,11, Vincent Zoete1,2,10, Jean-Paul Rivals12, Melita Irving1,2, Daniel E. Speiser1, Alexandre Harari1,2, David Gfeller1,2,6, Olivier Adotevi13, Francesco Ceppi9, George Coukos1,2, Pedro Romero1,2, Camilla Jandus1,2,3,4,5* 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. copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Adoptive T cell transfer (ACT) represents a promising, personalized immunotherapy of cancer (1) . While effector CD8 T lymphocytes are favored for targeting and eliminating malignant cells, emerging evidence suggests that the polyfunctional and cytotoxic subsets of CD4 T cells may be equally crucial in the immune response against cancer (2, 3) . In addition, the formation of the cluster of CD8 T cells–CD4 T cells–dendritic cells was shown to be indispensable to overcome CD8 T cell dysfunction upon ACT or immune checkpoint blockade (4) . Further, case reports have demonstrated that ACT of autologous CD4 T cells enables durable clinical responses inpatients with refractory melanoma (5) and metastatic epithelial cancer (6) . Moreover, T cell receptor (TCR)–engineered CD4 T cells targeting tumor antigens, such as MAGE-A3 (melanoma-associated antigen-A3), have shown encouraging tumor regressions following infusion (7) . The contributions of CD4 in the context of adoptive cell therapy can be multiple, from catalyzing the increased homing 1department of Oncology Unil chUv, University of lausanne, lausanne, Switzerland. 2ludwig institute for cancer Research, lausanne, Switzerland. 3department of Pathology and immunology, University of Geneva, Geneva, Switzerland. 4translational Research centre in Onco-hematology (cRtOh), University of Geneva, Geneva, Switzerland. 5Geneva centre for inflammation Research (GciR), University of Geneva, Geneva, Switzerland. 6SiB Swiss institute of Bioinformatics, lausanne, Switzerland. 7division of nephrology, Geneva University hospitals, Geneva, Switzerland. 8division of transplantation immunology, Geneva University hospitals, Geneva, Switzerland. 9Pediatric hematology-Oncology Unit, division of Pediatrics, department “WomanMother-child,” University hospital and lausanne University, lausanne, Switzerland. 10Molecular Modeling Group, SiB Swiss institute of Bioinformatics, lausanne, Switzerland. 11department of Oncology, Geneva University ho

FAQs

What role do CD4 T cells play in antitumor immunity compared with CD8 T cells?

The study notes that while CD8 T lymphocytes are often favored, polyfunctional and cytotoxic CD4 T cell subsets are increasingly recognized as crucial for effective antitumor responses.

How did the study identify NY-ESO-1–specific CD4 T cells?

Researchers screened HLA-DRB302:02 melanoma patients to find robust tumor-specific CD4 T cells and then analyzed NY-ESO-1(123–137)/HLA-DRB302:02–restricted CD4 T cell clones from blood and tumor tissue.

What therapeutic potential do the identified TCRs have?

When TCRs from these clones were transduced into primary CD4 T cells, they demonstrated direct antitumor efficacy in vitro and in vivo, supporting adoptive T cell transfer for NY-ESO-1–expressing cancers.

Sep 23, 2026

Uploaded by Aditya