Third-Generation Chimeric Antigen Receptor (CAR) T Cells in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) - Results from the Heidelberg Trial 1 (HD-CAR-1 trial)

Introduction Chimeric antigen receptor (CAR) T cell (CART) therapy has shown to be a new and very promising therapeutical method in patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). The investigator-initiated Heidelberg-CAR-T-cell-trial 1 (HD-CAR-1) evaluates both efficacy and safety of escalating doses of 3 rd-generation CD19-directed CARTs comprising CD28 and 4-1BB as costimulatory molecules in patients with r/r ALL and NHL. Leukapheresis, manufacturing, administration, patient monitoring and follow-up were all conducted in-house at the Heidelberg University Hospital. Methods Treatment was conducted with escalating doses of autologous 3 rd-generation CARTs after lymphodepletion with fludarabine (90 mg/m 2) and cyclophosphamide (1,500 mg/m 2) in patients with r/r acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or Non-Hodgkin's lymphoma (NHL), with subtype including diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) or mantle cell lymphoma (MCL). Treatment efficacy as well as occurrence of toxicities, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections or cytopenia, were evaluated. Following prior results regarding dose-dependent efficacy and excellent toxicity profile with dose levels (DL) I, II and III (10 6, 5×10 6 and 20×10 6 CARTs/m 2), a trial amendment was approved for treatment of patients with higher CART doses (DL IV, V and VI: 5x10 7, 10x10 7 and 20x10 7 CARTs/m 2). Results Overall, screening was performed for 32 patients. Two patients were considered screening failures due to rapidly progressive disease (PD) and uncontrolled hepatitis B infection, respectively; leading to 30 patients enrolled in the study. The HD-CAR-1 product was given to 27 patients (12 patients with ALL, four with CLL, four with MCL, five with DLBCL, and two with FL) in different dose levels (six patients with DL I, six patients with DL II, eight patients with DL III, 5 patients with DL IV, 2 patient with DL V). The CART product was not given to two patients due to PD and lethal septic complication, respectively. Severe CAR-T toxicity was rare, as only two patients developed CRS ≥ III°. Both patients received treatment with tocilizumab, while one was additionally treated with steroids. No ICANS ≥ III° were reported in the study. 54% of patients achieved a complete response (CR) with an overall response r