Background: A tandem chimeric antigen receptor (CAR) targeting CD20 and CD19 (pLTG1497) has shown superior efficacy as compared to each single-CAR in pre-clinical models. MB-CART2019.1 consists of autologous CD4 and CD8 enriched T-cells, which are transduced with a lentiviral vector that encodes the CAR construct for both CD20 and CD19 incorporating a 4-1BB co-stimulatory domain.
Aims: This first-in-human, Phase I study had the objective to assess feasibility, safety and toxicity of ex vivo generated MB-CART2019.1 in mainly elderly patients (pts) with relapsed or refractory (r/r) CD20 and CD19 positive aggressive B-cell Non-Hodgkin lymphoma (B-NHL) without curative treatment option (NCT03870945).
Methods: The trial included two predefined dose levels (DL1 1.0x106 and DL2 2.5x106 CAR T-cells/kg body weight (BW), respectively). In DL1 pts with multiple prior treatment lines were included while in DL2 the patient population was limited to pts with r/r DLBCL and 1 prior line of treatment who were transplant-ineligible. Fludarabine and cyclophosphamide were used for lymphodepletion. Infusion of fresh MB-CART2019.1 was scheduled 14 days after leukapheresis. The primary endpoint was to evaluate the maximum tolerated dose of MB-CART2019.1 as determined by dose limiting toxicities (DLT). Secondary endpoints included adverse events, overall response rate (ORR), maximum concentration (Cmax), area under the curve (AUCd0-d28), and persistence of CAR T-cells, measured by flow-cytometry.
Results: A total of 12 pts, 6 per dose level, have been treated in the trial after obtaining informed consent. Median age was 72 y (range 20, 78 y), with 8 pts >70 y. Histologies included aggressive B-NHL (9), transformed follicular lymphoma (2), and mantle cell lymphoma (1). No grade ≥3 cytokine release syndrome (CRS) or neurotoxicity were observed. Haematotoxicity was very limited with no anemia or thrombocytopenia ≥grade 3 beyond day 28 and intermittent neutropenia ≥grade 3 in only two pts beyond week 8 after treatment. No DLT were observed.
The ORR was 75% (3/6 pts in DL1 and 6/6 pts in DL2) with 5/12 pts (3/6 pts in DL1 and 2/6 pts in DL2) achieving PET-CT negative complete remission (CR) (CR-group). Among those 5 pts, all had ongoing CR as radiologically documented by PET-CT or CT at 12 months and all completed a 2-year follow-up visit without evidence of relapse as per investigator assessment. Patients with only partial response or stable disease as best overall response ultimately progressed.
All pts with CR had a Cmax ≥450 cells/µL with mean Cmax 1,092.5 cells/µL (range 460.1, 3,147.0) while pts with no CR had lower values with mean Cmax of 111.0 cells/µL (3.9, 458.0). Mean AUCd0-d28 was 7,901 d*cells/µL (2,399.2; 19,574.7) in the CR-group as opposed to mean AUCd0-d28 of 942.0 d*cells/µL (39.3; 3,471.62) in the non-CR group. Mean time of CAR T-cell persistence in the CR-group was 491 days (274, 736 d) and all 5 CR pts had detectable CAR T-cells beyond month 6.
Summary/Conclusion: As reported previously, recommended dose of MB-CART2019.1 is 2.5x106 CAR T-cells/kg BW. Importantly, all 5 pts with CR were still in CR 12 months after treatment and have now completed the 2-year follow-up visit without evidence of relapse. MB-CART2019.1 is currently challenging conventional immune-chemotherapy in a randomized Phase II trial for elderly, non-transplant eligible pts with first progression or relapse of aggressive B-NHL (NCT04844866).