Timing of Anti-PD-L1 Antibody Initiation Affects Efficacy/Toxicity of CD19 CAR-T Cell Therapy for Large B-Cell Lymphoma.

Over half of the patients treated with CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be due in part to PD-1/PD-L1-associated CAR-T cell dysfunction. We report data from a phase 1 clinical trial, in which adults with LBCL were treated with autologous CD19 CAR-T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR-T cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome, and inferior efficacy, which was associated with slower accumulation of CAR-T cells and lower concentrations of inflammatory cytokines in blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR-T cell accumulation in blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR-T cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR-T cell kinetics, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR-T cells in blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR-T cell immunotherapy for adults with LBCL.