A Phase I Dose Finding Trial of MB-CART20.1 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (2022)

Introduction: Approved Chimeric Antigen Receptor (CAR) T-cell therapies in refractory or relapsed B-cell Non-Hodgkin lymphoma (r/r B-NHL) target CD19; however, their efficacy is limited to about half of the patients treated. We thus developed a CAR targeting CD20 (MB-CART20.1) consisting of CAR transduced CD4 /CD8 enriched T-cells, derived from an autologous leukapheresis. Here, we report on the first part of a phase I first-in-human clinical trial that evaluates the safety of MB-CART20.1 in patients with r/r B-NHL. Methods: Patients with r/r B-NHL with no curative treatment option were eligible for this phase I multi-center, open label, dose escalation trial of MB-CART20.1 (EudraCT 2017-000121-12). The primary objective was to determine safety of MB-CART20.1. Secondary objectives included response to treatment, phenotype and persistence of MB-CART20.1. The primary endpoint was determination of the maximum tolerated dose (MTD), defined as the highest dose level at which < 33% of patients experience Dose Limiting Toxicities (DLTs) until day 28 post infusion (follow-up safety period). Patient leukapheresis products were enriched for CD4/CD8 T-cells, transduced with the vector and expanded using the CliniMACS Prodigy System.. Apheresis and the MB-CART20.1 were fresh products with a turnaround time of 14 days. Patients underwent lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), each from day -5 to day -3. Dose escalation was planned with 3 + 3 patients at Dose Level (DL) 0 (1x105 CAR T-cells/kg BW), followed by DL1 (1x106 CAR T-cells/kg BW ) and DL2 (3x106 CAR T-cells/kg BW) with 6 + 3 patients, each. Results: In total 10 patients were treated. 9 patients were included in this analysis. 1 patient was treated with an out of specification product, these data are not included. 7 patients were enrolled at DL0 and 2 at DL1. 8 of 9 patients completed the follow-up safety period. At DL0, 3 of 7 patients experienced CRS (grade I) starting 1 to 10 days post infusion. One CRS case was managed with tocilizumab. This patient further developed CAR T-cell related encephalopathy syndrome (CRES; grade II) and bone marrow aplasia (grade III). On day 17 post infusion the patient died because of a septic shock. The Safety Monitoring Board thus recommended to extend DL0 with 3 additional patients. In this extension cohort, no further neurotoxicity or any DLT occurred. 1 of 7 patients achieved complete response (CR), remained in remission until month 12 and then entered long-term follow-up. 5 patients progressed at 4 weeks (n=2), 12 weeks (n=2) and 6 months (n=1) post infusion, respectively. Analysis of expansion for the 3 patients reaching at least partial response (PR) within 12 weeks (responders) showed a notable increase of the maximum cell concentration (Cmax, values between 3,1 to 104,7 cells/µl), as well as an enhanced area under the curve from day 0 to 28 (AUC D0-28, between 28,5 and 1273,0 days/cells/µl). This increase of values was not observed in the 3 non-responders. Time to Cmax is similar between responders and non-responders (mean 16 days). At DL1, 2 of 2 patients experienced CRS shortly post infusion (grade I and II respectively). Tocilizumab was used in one patient. Neither DLT nor ICANS occurred. Short-lived Grade III and IV neutropenia was observed in both patients. Both patients completed the active part of the trial (12 months post infusion) with CR, entered the long-term follow-up and remained in CR until data cut-off. Analysis of expansion showed an increase of Cmax with 198,6 and 79,8 cells/µl, respectively and AUC D0-28 with 2495,0 and 610,1 days/cells/µl. Time to Cmax is 14 days for both patients. The sponsor stopped the trial early due to the COVID pandemic with relevant impact on enrollment and study conduct. In addition there are no current plans for further development of this vector. Conclusions: No DLT was observed in this first trial of a CD20 targeting CAR T-cell product in r/r B-NHL patients; however, early termination of the trial does not allow conclusions on a MTD. In total 3 patients achieved a CR and remained in remission for at least one year. The two patients treated at the higher DL, achieved a CR indicating a dose-response correlation. The results strongly support further evaluation of MB-CART20.1 in r/r B-cell NHL.