CD19-Specific CAR-T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor is Effective in Patients with PD-L1 Positive B-Cell Lymphoma.

Purpose: CD19-specific chimeric antigen receptor (CAR)-T cell therapy is effective against refractory or relapsed (R/R) B-cell lymphoma, but the efficacy is hindered by the existence of PD-1/PD-L1 pathway. Experimental Design: Here we generated a novel anti-CD19 CAR expressing PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR). We then conducted a phase 1b study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1+ B-cell lymphoma. Results: We found that CD19-PD-1/CD28-CAR T cells had superior T-cell proliferation, cytokine production, and sequentially, capability of killing PD-L1+ B-cell lymphoma cells in vitro and in vivo relative to the prototype CD19-CAR T cells. Among total of 17 adult patients with R/R lymphoma received the CAR-T therapy, 10 patients had objective response (58.8%), including 7 patients with complete remission (41.2%). At a median follow-up 15 months, median overall survival for all patients was not reached. Remarkably, no severe neurological toxicity or cytokine-release syndrome was observed. Conclusions: This first-in-human study demonstrates the tolerability, safety, and encouraging efficacy of CD19-PD-1/CD28-CART in PD-L1+ large B-cell lymphoma.