Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.

102 Background: We are conducting a phase I/II trial in which patients (pts) with relapsed or refractory (R/R) CD19+ B cell malignancies receive CD19 CAR-T cells comprised of a defined ratio of CD8+ and CD4+ CAR-T cells. Methods: Pts received lymphodepleting chemotherapy followed by infusion of a 1:1 ratio of CD8+:CD4+ CAR-T cells at one of 3 dose levels (2x105 to 2x107 CAR-T cells/kg). No pts were excluded due to lymphopenia (ALC < 0.5 in 22% of pts), circulating tumor or poor in vitro T cell proliferation. Results: Ninety pts with ALL (n = 36), NHL (n = 41) or CLL (n = 13) received CAR-T cells. Thirty-one of 33 ALL pts (94%) that have had restaging achieved CR by marrow flow cytometry. Two of 31 pts had molecular MRD. In vivo CAR-T cell expansion and persistence, and DFS were superior in pts who received cyclophosphamide (Cy) and fludarabine (Flu) lymphodepletion compared to those who received Cy without Flu. CAR-T cell persistence was limited in patients not receiving Flu by immune responses to the murine scFv of the CAR. In NHL, the ORR for pts treated with Cy/Flu and CAR-T cells at the maximally tolerated cell dose (n = 19; 2x106/kg) was 84% (47% CR). CAR-T cell expansion and persistence, and OS and PFS were better in Cy/Flu pts compared to those who received Cy alone (ORR 50%, CR 8%, n = 12). Remissions are ongoing in 9 of 10 Cy/Flu treated pts who achieved CR (range 1-9 months follow-up). All CLL pts had received prior ibrutinib. CAR-T cell therapy eliminated CLL from the marrow in 10 of 12 restaged pts (83%) and 6 (50%) achieved CR (Lugano criteria). None of the CLL pts who achieved CR has relapsed. In 87 pts evaluated for toxicity the rates of severe cytokine release syndrome (sCRS) and grade ≥ 3 neurotoxicity were 16% and 31%, respectively. Four pts (4%) died of complications of CRS and 1 pt experienced irreversible neurotoxicity. We identified serum biomarkers on day 1 after CAR-T cell infusion that correlated with subsequent sCRS or grade ≥ 3 neurotoxicity in ALL and NHL pts, allowing rational design of early intervention studies in high-risk pts. Conclusions: Adoptive therapy with CD19 CAR-T cells of defined subset composition results in durable CR in a high fraction of pts with R/R ALL, NHL and CLL. Clinical trial information: NCT01865617.