In this review, Montel-Hagen and Crooks discuss past and present research supporting the goal of developing off-the-shelf T cell products for cancer immunotherapy from pluripotent stem cells (PSCs). PSCs can be genetically modified with prearranged TCR or CAR constructs, have the unique capacity for unlimited self-renewal, and can be differentiated into functional tumor-specific T cells.
The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T cell immunotherapy. After directing PSC through mesoderm and early hematopoietic developmental stages, commitment to the T cell lineage has been achieved by several groups using co-culture with stromal cells that express a notch-ligand, recapitulating the critical signals that initiate the first stages of normal T cell differentiation in the thymus. However positive selection and the production of mature T cells from human PSC has been limited to date. Nonetheless, T lineage cells have been generated from PSC with tumor antigen-specificity either through a pre-arranged clonal T cell receptor (TCR) or lentiviral mediated expression of Chimeric Antigen Receptors (CAR). The recent development of a 3D artificial organoid model has demonstrated that PSC can generate mature conventional T cells that are fully functional and express a diverse T cell receptor (TCR) repertoire. Introduction of a transgenic TCR at the PSC stage allows production of tumor antigen-specific, mature conventional T cells. The tools of gene editing in PSC are ideally suited to produce off-the-shelf universal products for T cell immunotherapy. In this review we describe the studies that have led to this exciting moment in PSC biology and translation to clinical applications.