RNA Therapeutics for Improving CAR T-cell Safety and Efficacy

Autologous chimeric antigen receptor (CAR) T cells have recently emerged as potent tools in the fight against cancer, with promising therapeutic efficacy against hematological malignancies. However, several limitations hamper their widespread clinical use, including availability of target antigen, severe toxic effects, primary and secondary resistance, heterogeneous quality of autologous T cells, variable persistence, and low activity against solid tumors. Development of allogeneic off-the-shelf CAR T cells could help address some of these limitations but is impeded by alloimmunity with either rejection and limited expansion of allo-CAR T cells or CAR T cells versus host reactions. RNA therapeutics, such as small interfering RNAs, microRNAs, and antisense oligonucleotides, are able to silence transcripts in a sequence-specific and proliferation-sensitive way, which may offer a way to overcome some of the challenges facing CAR T-cell development and clinical utility. Here, we review how different RNA therapeutics or a combination of RNA therapeutics and genetic engineering could be harnessed to improve the safety and efficacy of autologous and allogeneic CAR T-cell therapy.