Allogeneic "Off-the-Shelf" CAR T cells: Challenges and advances

Chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical efficacy in B cell malignancies and multiple myeloma, leading to the approval of six CAR T cell products by the U.S. Food and Drug Administration (FDA) to date. However, broad application of these autologous (patient-derived) CAR T cells is limited by several factors, including high production costs, inconsistent product quality, contamination of the cell product with malignant cells, manufacturing failure especially in heavily pre-treated patients, and lengthy manufacturing times resulting in subsequent treatment delay. A potential solution to these barriers lies in the use of allogeneic "off-the-shelf" CAR T cells produced from healthy donors. Many efforts are underway to make allogeneic CAR T cells a safe and efficacious therapeutic option. In this review, we will discuss the major challenges that have to be addressed to successfully develop allogeneic CAR T cell therapies, specifically graft-versus-host disease (GVHD) and host-mediated immune rejection of the donor cells. Furthermore, we will summarize approaches that have been utilized to overcome these limitations, focusing on the use of gene editing technologies and strategies employing alternative cell populations as the source for allogeneic CAR T cell production.