Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors

Monospecific Chimeric Antigen Receptor (CAR) T cell therapy against hematological malignancies targeting specific tumor-associated antigen (TAA) has gained clinical success in recent years. Despite their clinical outcomes, challenges including antigen escape, time and labor-intensive manufacturing process, and diminished efficacy especially against solid tumors persist. While allogeneic monospecific "off-the-shelf" CAR T cell therapy from healthy donors with knockout of alloreactive genes using gene editing tools such as CRISPR/Cas9 or TALEN has been evaluated to overcome manufacturing challenges, these allogeneic CAR T cells still face antigen escape. As such, adapter-based CAR T cells that can be redirected by small-molecule adapters to target multiple TAAs have emerged as an alternative therapeutic platform to overcome antigen escape. However, autologous adapter-based CAR T cell manufacturing remains time and labor intensive and scales poorly. Furthermore, chemotherapy-induced T cell dysfunction may compromise both manufacturing and efficacy of autologous CAR T cells. In this comprehensive review, we highlight advantages and limitations of the adapter-based CAR T platform and discuss how allogeneic manufacturing can be applied to adapter-based CAR T as a potential "off-the-shelf" therapeutic for treating multiple cancer types and overcome antigen escape.