A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence

Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8 + T cells engineered to express a Wilms Tumor Antigen 1-specific T-ce...

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Vydáno v:	Nature communications Ročník 16; číslo 1; s. 5214 - 20
Hlavní autoři:	Mazziotta, Francesco, Martin, Lauren E., Egan, Daniel N., Bar, Merav, Kinsella, Sinéad, Paulson, Kelly G., Voillet, Valentin, Lahman, Miranda C., Hunter, Daniel, Schmitt, Thomas M., Duerkopp, Natalie, Yeung, Cecilia C. S., Tang, Tzu-Hao, Gottardo, Raphael, Asano, Yuta, Wilcox, Elise C., Lee, Bo, Zhang, Tianzi, Lopedote, Paolo, Penter, Livius, Wu, Catherine J., Milano, Filippo, Greenberg, Philip D., Chapuis, Aude G.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 05.06.2025 Nature Publishing Group Nature Portfolio
Témata:	38 38/91 49 49/91 631/250/2520 631/67 Acute myeloid leukemia Adult Aged Allografts CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell therapy Cytomegalovirus Cytomegalovirus - immunology Effectiveness Epstein-Barr virus Female Gene therapy Genetic Therapy - adverse effects Genetic Therapy - methods Health services Hematopoietic Stem Cell Transplantation - adverse effects Hematopoietic stem cells Herpesvirus 4, Human - immunology Humanities and Social Sciences Humans Immunotherapy Killer Cells, Natural - immunology Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - immunology Leukemia, Myeloid, Acute - therapy Lymphocytes Lymphocytes T Male Middle Aged multidisciplinary Patients Phenotypes Receptors Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology Risk groups Science Science (multidisciplinary) Solid tumors Stem cell transplantation T cell receptors T-Lymphocytes - immunology Transplantation Transplantation, Homologous Treatment Outcome Tumors WT1 Proteins - genetics WT1 Proteins - immunology Young Adult
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8 + T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (T TCR-C4 ) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific T TCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, T TCR-C4 cells did not clearly improve outcomes despite EBV-specific T TCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific T TCR-C4 . Investigating the fate of persisting T TCR-C4 , we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting T TCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML. Relapsed and/or refractory acute myeloid leukemia (AML) postallogeneic hematopoietic cell transplantation has limited treatment options. Here the authors report the clinical results and immune correlates of a phase I/II trial of adoptively transferred virus-specific donor CD8 + T cells engineered to express a WT1-specific T cell receptor in patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-60394-0