CAR-T therapy dilemma and innovative design strategies for next generation
Zhiwei Wang, Peixian Li, Xiaoyu Zeng, Jing Guo, Cheng Zhang, Zusen Fan, Zhiwei Wang, Pingping Zhu, Zhenzhen Chen
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy has shown remarkable curative effects on hematological tumors, driving the exponential growth in CAR-T-related research. Although CD19-targeting CAR-T-cell therapy has displayed remarkable promise in clinical trials, many obstacles are arising that limit its therapeutic efficacy in tumor immunotherapy. The "dilemma" of CAR-T cell-based tumor therapy includes lethal cytotoxicity, restricted trafficking, limited tumor infiltration, an immunosuppressive microenvironment, immune resistance and limited potency. The solution to CAR-T-cell therapy's dilemma requires interdisciplinary strategies, including synthetic biology-based ON/OFF switch, bioinstructive scaffolds, nanomaterials, oncolytic viruses, CRISPR screening, intestinal microbiota and its metabolites. In this review, we will introduce and summarize these interdisciplinary-based innovative technologies for the next generation CAR-T-cell design and delivery to overcome the key barriers of current CAR-T cells.