SUMOylation inhibition potentiates CAR T activity against multiple myeloma (RNA-Seq)

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against hematologic malignancies; however, tumor relapse occurs commonly due to T cell dysfunction presenting as exhaustion and loss of effector function. Here, we identified SUMOylation inhibition promoted T cell effector function and prevented T cell exhaustion. Combination of SUMO E1 inhibitor TAK-981, significantly potentiated CAR T cell anti-tumor activity and improved persistence of CAR-presenting T cells in vivo, presenting a potent novel therapeutic approach. Overall design: CS1-CAR T cells were treated with DMSO (Vehicle, Veh) or 0.1µM TAK-981 (TAK) for 16 h, then CD4+ and CD8+ subsets of CS1 CAR T cells treated were purified by FACS sorting after staining with CD4 and CD8 antibodies. In co-culture experiment, CS1-CAR T cells were treated with vehicle (Veh) or TAK-981 (0.1µM, TAK) for 16 h. CAR T were spin down and washed off compound, then CAR T cells were cultured with MM1S-Luc cells at 1:1 ratio for 24 h. Cell mixtures were harvested then CD4+ and CD8+ CAR T cells were purified by FACS sorting after staining with CD4 and CD8. In both experiments, CS1 CAR T cells generated from two individual donors were used as biological replicates.