The Preliminary Study Of The Novel CAR-T Function Of IL-21-CCL19

CAR-T(Chimeric antigen receptor-T)cells have shown remarkable efficacy in cancer immunotherapy,particularly in the treatment of blood cancers,but how to translate this success to solid malignancies remains elusive.Although inefficient tumor trafficking and various immunosuppressive barriers including factors that regulate CAR T cells expansion,persistence,trafficking,and fate within tumors,can impede CAR-T cell effector responses,the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions.Optimal T cell activation and proliferation requires multiple signals,including T cell receptor(TCR)engagement(signal 1),co-stimulation(signal 2)and cytokine engagement(signal 3).However,CAR constructs currently being tested in the clinic contain a CD3z(TCR signaling)domain and co-stimulatory domain(s)but not a domain that transmits signal 3.Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation.This new-generation CD19 CAR encodes interleukin(IL)-21 and CCL19,together with the TCR signaling(CD3z)and co-stimulatory(CD28)domains(hereafter referred to as 21×19 CAR).The 21×19 CAR-T cells showed antigen-dependent activation and secrete IL-21 which promoted their proliferation and prevented terminal differentiation in vitro.21×19 CAR-T cells release more IL-2,and CCL19 which improved the migration of response-T cells.Taken together,these results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted.