Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo
Molecular Therapy - Methods & Clinical Development(2021)
摘要
Although chimeric antigen receptor T (CAR-T) cell therapy achieves high remission rates, challenges (e.g., toxicity management and relapse prevention) remain. The major risks are cytokine release syndrome and related neurological toxicity. The influence of the CAR surface density on the efficacy/safety of CAR-T cell therapy and the factors determining CAR density were not elucidated comprehensively. Here, we discovered that the use of the MND promoter increased the transduction rate and reduced the CAR surface density. Additionally, MND-driven CAR-T cells had prolonged antileukemia activity in a mouse model. In an initial dual-armed anti-CD19 CAR-T cell pilot study (ClinicalTrials.gov: NCT03840317), eight and six subjects were infused with MND and EF1 alpha promoter-driven autologous CAR-T cells (3 x 10(5) CAR-T cells/kg), respectively. MND subjects developed mild fever and lower interferon gamma (IFN-gamma) concentrations than in the EF1A19 group. All but one subject in each cohort reached minimal residual disease (MRD)-negative complete remission after the first month of evaluation. These results represent the first comprehensive study on the promoter-driven modulation of CAR-T cell functionality. These findings encourage further evaluation of the potential of the MND promoter to drive CAR-T cells as a broadly applicable cellular product for anticancer immunotherapy.
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关键词
B-ALL,MND,CAR density,promoter usage,CAR-T,CD19
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