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<p>Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861</p>

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Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

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  • Theodore S. Nowicki,
  • Nataly Naser Al Deen,
  • Cole W. Peters,
  • Begoña Comin-Anduix,
  • Egmidio Medina,
  • Cristina Puig-Saus,
  • Ignacio Baselga Carretero,
  • Paula Kaplan-Lefko,
  • Mignonette H. Macabali,
  • Ivan Perez Garcilazo,
  • Daniel Chen,
  • Jia Pang,
  • Beata Berent-Maoz,
  • Salem Haile,
  • Jonathan Rodriguez,
  • Moe Kawakami,
  • Conner K. Kidd,
  • Ameya Champhekar,
  • Giuseppe Carlucci,
  • Agustin Vega-Crespo,
  • Bartosz Chmielowski,
  • Arun Singh,
  • Noah Federman,
  • Gary M. Schiller,
  • Sarah J. Larson,
  • Martin Allen-Auerbach,
  • Alexandra M. Klomhaus,
  • Jerome Zack,
  • David Baltimore,
  • Lili Yang,
  • Donald B. Kohn,
  • Owen N. Witte,
  • Antoni Ribas

摘要

Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861