Beyond conventional adoptive T-cell therapy.

Abstract

Reconstitution of the T-cell compartment is essential in the treatment of several immune disorders. Similarly, individuals with hematologic malignancies who are undergoing allogeneic hematopoietic stem cell transplantation experience prolonged T-cell deficiencies, which increase their risk of infections and relapses. Various strategies for addressing T-cell deficiencies are based on adoptive T-cell therapies. However, challenges related to specificity, safety, scalability, and manufacturing have yet to be overcome. Human T lymphoid progenitor-based immunotherapy might be a valuable, complementary approach for increasing the effectiveness of current treatments for T-cell deficiencies. We have developed a feeder-free culture system that leverages a human DLL4-Fc fusion protein (Notch ligand) to generate human T lymphoid progenitors from CD34⁺ hematopoietic stem and progenitor cells within 7 days. The cell product, called ProTcell, is composed mainly of cells expressing CD7, chemokine receptor proteins (eg, CCR9), and adhesion molecules (eg, L-selectin). After injection in NSG mice, ProTcell can differentiate and be educated in the thymus to generate simple positive T cells. Here, we summarize the current state of preclinical and clinical research using this approach, highlighting its potential advantages and current limitations for immune reconstitution therapies.