Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny

• Published in: Nature communications Vol. 16; no. 1; pp. 5599 - 14
• Main Authors: Nowicki, Theodore S., Deen, Nataly Naser Al, Peters, Cole W., Comin-Anduix, Begoña, Medina, Egmidio, Puig-Saus, Cristina, Carretero, Ignacio Baselga, Kaplan-Lefko, Paula, Macabali, Mignonette H., Garcilazo, Ivan Perez, Chen, Daniel, Pang, Jia, Berent-Maoz, Beata, Haile, Salem, Rodriguez, Jonathan, Kawakami, Moe, Kidd, Conner K., Champhekar, Ameya, Carlucci, Giuseppe, Vega-Crespo, Agustin, Chmielowski, Bartosz, Singh, Arun, Federman, Noah, Schiller, Gary M., Larson, Sarah J., Allen-Auerbach, Martin, Klomhaus, Alexandra M., Zack, Jerome, Baltimore, David, Yang, Lili, Kohn, Donald B., Witte, Owen N., Ribas, Antoni
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38/91; 42/100; 42/44; 45; 631/250/251; 631/532/1542; 631/67/1059/2325; 692/4028/67/1798; Ablation; Adoptive transfer; Anergy; Anticancer properties; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antitumor activity; Bone marrow; Cancer therapies; Cell therapy; Chemotherapy; Clinical trials; Cytomegalovirus; Effectiveness; Female; Genetic engineering; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Human subjects; Humanities and Social Sciences; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Kinases; Lymphocytes; Lymphocytes T; Male; Malignancy; Manufacturing; Membrane Proteins - genetics; Membrane Proteins - immunology; Metastasis; multidisciplinary; Neoplasms - immunology; Neoplasms - therapy; Patients; Phenotypes; Progenitor cells; Progeny; Radiation; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Sarcoma; Science; Science (multidisciplinary); Solid tumors; Stem cells; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Tomography; Tumors; White people
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60816-z

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 Therapeutic T cells engineered to recognize tumour antigens are frequently short-lived and acquire unfavourable phenotypes in tumours. Here authors show that a tandem approach using autologous T cells targeted against the tumour antigen NY-ESO-1, followed by transfer of hematopoietic stem cells with the same specificity in the clinical trial NCT03240861, provides a safe and promising therapeutic option.