Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor T Cells: The Intersection of Stem Cells and Immunotherapy.

Abstract

Chimeric antigen receptor (CAR) T cell therapy is a promising cell-based immunotherapy applicable to various cancers. High cost of production, immune rejection, heterogeneity of cell product, limited cell source, limited expandability, and relatively long production time have created the need to achieve a universal allogeneic CAR-T cell product for "off-the-shelf" application. Since the innovation of induced pluripotent stem cells (iPSCs) by Yamanaka et al., extensive efforts have been made to prepare an unlimited cell source for regenerative medicine, that is, immunotherapy. In the autologous grafting approach, iPSCs prepare the desired cell source for generating autologous CAR-T cells through more accessible and available sources. In addition, generating iPSC-derived CAR-T cells is a promising approach to achieving a suitable source for producing an allogeneic CAR-T cell product. In brief, the first step is reprogramming somatic cells (accessible from peripheral blood, skin, etc.) to iPSCs. In the next step, CAR expression and T cell lineage differentiation should be applied in different arrangements. In addition, in an allogeneic manner, human leukocyte antigen/T cell receptor (TCR) deficiency should be applied in iPSC colonies. The allogeneic iPSC-derived CAR-T cell experiments showed that simultaneous performance of HLA/TCR deficiency, CAR expression, and T cell lineage differentiation could bring the production to the highest efficacy in generating allogeneic iPSC-derived CAR-T cells.