Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny

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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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

Date: 2025
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DOI: 10.1038/s41467-025-60816-z

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