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

Francesco Mazziotta, Lauren E. Martin, Daniel N. Egan, Merav Bar, Sinéad Kinsella, Kelly G. Paulson, Valentin Voillet, Miranda C. Lahman, Daniel Hunter, Thomas M. Schmitt, Natalie Duerkopp, Cecilia C. S. Yeung, Tzu-Hao Tang, Raphael Gottardo, Yuta Asano, Elise C. Wilcox, Bo Lee, Tianzi Zhang, Paolo Lopedote, Livius Penter, Catherine J. Wu, Filippo Milano, Philip D. Greenberg and Aude G. Chapuis ()
Additional contact information
Francesco Mazziotta: Fred Hutchinson Cancer Center
Lauren E. Martin: Fred Hutchinson Cancer Center
Daniel N. Egan: Fred Hutchinson Cancer Center
Merav Bar: Fred Hutchinson Cancer Center
Sinéad Kinsella: Fred Hutchinson Cancer Center
Kelly G. Paulson: Fred Hutchinson Cancer Center
Valentin Voillet: Fred Hutchinson Cancer Center
Miranda C. Lahman: Fred Hutchinson Cancer Center
Daniel Hunter: Fred Hutchinson Cancer Center
Thomas M. Schmitt: Fred Hutchinson Cancer Center
Natalie Duerkopp: Fred Hutchinson Cancer Center
Cecilia C. S. Yeung: Fred Hutchinson Cancer Center
Tzu-Hao Tang: Fred Hutchinson Cancer Center
Raphael Gottardo: Lausanne University Hospital
Yuta Asano: Fred Hutchinson Cancer Center
Elise C. Wilcox: Fred Hutchinson Cancer Center
Bo Lee: Fred Hutchinson Cancer Center
Tianzi Zhang: Fred Hutchinson Cancer Center
Paolo Lopedote: Boston University
Livius Penter: Dana-Farber Cancer Institute
Catherine J. Wu: Dana-Farber Cancer Institute
Filippo Milano: Fred Hutchinson Cancer Center
Philip D. Greenberg: Fred Hutchinson Cancer Center
Aude G. Chapuis: Fred Hutchinson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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 (TTCR-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 TTCR-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, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-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 TTCR-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.

Date: 2025
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DOI: 10.1038/s41467-025-60394-0

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