Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny
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
Article Details
Authors (33)
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
Department of Microbiology, Immunology & Molecular Genetics, University of California
Donald B. Kohn
Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles
Owen N. Witte
Department of Molecular and Medical Pharmacology, University of California
Antoni Ribas