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<p>Immune-based cell therapy offers a promising approach to cancer treatment. While autologous chimeric antigen receptor (CAR) T cells have shown success, production is time-consuming, costly and patient specific. Gamma–delta (γδ) T cells are promising for ‘off-the-shelf’ CAR T cell therapy. However, clinical translation of γδ CAR T cells is hampered by low frequency, resistance to genetic manipulation and advanced differentiation after expansion, limiting therapeutic feasibility. Here we demonstrate a method for in vitro activation and expansion of peripheral blood γδ T cells, facilitating high rates of gene editing and efficient CAR integration. Using artificial antigen-presenting cells, we produce minimally differentiated, highly functional γδ CAR T cells. By targeting a US Food and Drug Administration-approved CD19 CAR to the CCR5 locus, we generate CCR5-deficient γδ CD19 CAR T cells (γδ CCR5KI-CAR19), which demonstrated resistance to HIV-mediated depletion and robust antitumour responses against B cell lymphoma and leukaemia. γδ CCR5KI-CAR19 T cells enable the immunotherapy of HIV-associated B cell malignancies. These studies provide preclinical evidence supporting large-scale development of potent allogeneic γδ CAR T cells for diverse immunotherapies.</p>

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CCR5-targeted allogeneic gamma–delta CD19 chimeric antigen receptor T cells for HIV-associated B cell-malignancy immunotherapy

  • 期刊论文

  • 发表日期：

    2025年10月21日

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  • Ángel Ramírez-Fernández,
  • Alexander J. Dimitri,
  • Fang Chen,
  • Robert Bartoszek,
  • Gregory M. Chen,
  • Laura Córdoba-Espejo,
  • Yuqi Zhou,
  • Yun-hsin Tang,
  • Chien-Ting Lin,
  • Reyes Acosta,
  • John Scholler,
  • Guido Ghilardi,
  • Patrizia Porazzi,
  • Mireia Pellicer,
  • Núria Profitós-Pelejà,
  • Stefan K. Barta,
  • Anne Chew,
  • Julie K. Jadlowsky,
  • Vanessa E. Gonzalez,
  • Donald L. Siegel,
  • Bruce L. Levine,
  • Gaël Roué,
  • Marco Ruella,
  • Michael T. Lotze,
  • Carl H. June,
  • James L. Riley,
  • Joseph A. Fraietta

摘要

Immune-based cell therapy offers a promising approach to cancer treatment. While autologous chimeric antigen receptor (CAR) T cells have shown success, production is time-consuming, costly and patient specific. Gamma–delta (γδ) T cells are promising for ‘off-the-shelf’ CAR T cell therapy. However, clinical translation of γδ CAR T cells is hampered by low frequency, resistance to genetic manipulation and advanced differentiation after expansion, limiting therapeutic feasibility. Here we demonstrate a method for in vitro activation and expansion of peripheral blood γδ T cells, facilitating high rates of gene editing and efficient CAR integration. Using artificial antigen-presenting cells, we produce minimally differentiated, highly functional γδ CAR T cells. By targeting a US Food and Drug Administration-approved CD19 CAR to the CCR5 locus, we generate CCR5-deficient γδ CD19 CAR T cells (γδ CCR5KI-CAR19), which demonstrated resistance to HIV-mediated depletion and robust antitumour responses against B cell lymphoma and leukaemia. γδ CCR5KI-CAR19 T cells enable the immunotherapy of HIV-associated B cell malignancies. These studies provide preclinical evidence supporting large-scale development of potent allogeneic γδ CAR T cells for diverse immunotherapies.