Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny

Area of Science:

• Oncology
• Immunotherapy
• Cellular Therapy

Background:

• Adoptive T cell therapy shows promise for malignancies but suffers from poor T cell persistence and functionality, leading to relapse.
• There is a critical need for cell therapy strategies that ensure sustained antitumor efficacy and long-term patient benefit.

Purpose of the Study:

• To evaluate the safety and efficacy of a tandem cell therapy combining autologous T cells and engineered hematopoietic stem cells (HSCs) expressing the NY-ESO-1 T cell receptor (TCR) in a phase I clinical trial.
• To assess the potential of engineered HSCs to generate a self-renewing population of functional, tumor-specific T cells for solid tumor treatment.

Main Methods:

• A first-in-human phase I clinical trial (NCT03240861) was conducted involving patients with solid tumors.
• Participants received tandem cell therapy with autologous T cells and HSCs genetically engineered to express the NY-ESO-1 TCR.
• The persistence, functionality, and differentiation status of the transgenic T cells were monitored post-therapy.

Main Results:

• The tandem cell therapy was found to be safe and feasible in human participants.
• Initial tumor regression activity was observed in patients treated with this approach.
• T cell progeny derived from engineered HSC progenitors successfully generated circulating, tumor-antigen-specific T cells that maintained antitumor functionality without anergy or exhaustion.

Conclusions:

• Engineered HSCs can serve as a source for sustained production of functional, tumor-specific T cells in vivo.
• This transgenic HSC approach offers a promising strategy for developing a self-renewing cellular immunotherapy for solid tumors.
• The findings support the utility of this novel cell therapy for achieving long-term antitumor efficacy.