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<p>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<sup>+</sup> T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (T<sub>TCR-C4</sub>) 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<sub>TCR-C4</sub> 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<sub>TCR-C4</sub> cells did not clearly improve outcomes despite EBV-specific T<sub>TCR-C4</sub> cells showing enhanced potential for prolonged persistence compared to CMV-specific T<sub>TCR-C4</sub>. Investigating the fate of persisting T<sub>TCR-C4</sub>, 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<sub>TCR-C4</sub> 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.</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月5日

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  • 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,
  • Aude G. Chapuis

摘要

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.