Responses to CAR T cell therapy currently range from efficacious to severely toxic. With the goal of developing methods to control activity, Yang et al. developed two molecular modules that, when transfected into CAR T cells, render CAR expression responsive to resveratrol (res) – a natural product present in the human diet. One module mediates res-dependent and titratable repression of anti-CD19 CAR T cell activation both in vitro and in a mouse model. Conversely, the other module imposes a res requirement for both in vitro and in vivo CAR T cell activity. This res control system establishes a proof of concept for a strategy to calibrate CAR T cell activity.
Contributed by Margot O’Toole
ABSTRACT: Chimeric antigen receptor (CAR)-engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)-responsive transactivator and a transrepressor to develop a repressible transgene expression (RES(rep)) device and an inducible transgene expression (RES(ind)) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RES(rep)-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RES(ind)-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RES(ind)-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RES(rep) and RES(ind) devices as effective tools for transgene expression and illustrates the potential of RES(rep)-CAR and RES(ind)-CAR devices to enhance patient safety in precision cancer immunotherapies.
Author Info: (1) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sc
Author Info: (1) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. (2) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. (3) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. (4) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. (5) Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA (6) Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China. (7) Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; hfye@bio.ecnu.edu.cn.
