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
- Antoni Ribas
2025-07-01
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