Promising Safety and Anti-Lymphoma Efficacy of Autologous Pmb-CT01 (BAFFRCAR T Cell) Therapy in a First-in-Human Phase 1 Study
Authors: Budde L. Elizabeth , Del Real Marissa Morales , Baird John H. , Chen Lu , Song Joo Y. , Kambhampati Swetha , Macias Alan , Kim Teresa , Dulan Sylvia , Barva Baishakhi , Puverel Sandrine , Tiemann Katrin , Cheng Hazel Ting-Ying , Forman Stephen J. , Kwak Larry W. 
Published: December 2023

Introduction: CD19 chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment landscape of B cell lymphoma. However, a significant number of patients with aggressive B cell lymphoma (aBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL) still relapse or have refractory disease after autologous CD19CAR T cell therapy, highlighting the urgent unmet need to seek alternative approaches to improve the outcomes. BAFF-R signaling is considered a driver of B cell and malignant growth and survival. This feature may limit the capacity of B cell tumors to evade therapy by loss of BAFF-R expression. Recent work (Qin et al., Sci Transl Med. 2019) has shown that BAFF-R expression is independent of CD19 expression on malignant B cells and that CAR T cells targeting BAFF-R were able to effectively eliminate various B cell malignancies in the preclinical setting. Here we report the initial results from the first 3 patients treated on an ongoing phase 1, first-in-human clinical trial (NCT05370430) evaluating the safety and efficacy of autologous BAFFRCAR T cells in patients with B cell lymphoma.

Study Design and Methods: Our studyis a phase 1, single center, open label, therapeutic trial. PMB-CT01 is a T N/ SCM-enriched BAFFR.41BB.z.EGFRt-CAR T cell therapy which was previously described (Qin et al. Sci Transl Med. 2019). There are 3 dose levels (DL) in the dose escalation phase including 50x10 6 (DL1), 200x10 6 (DL2), and 600x10 6 (DL3) CAR T cells. The lymphodepletion regimen consists of cyclophosphamide 500 mg/m 2/day and fludarabine 30 mg/m 2/day for 3 days.

The primary endpoints are the incidence of adverse events and the determination of the maximum tolerated dose. Secondary endpoints include disease response, incidence of negative minimal residual disease (MRD), progression-free survival, and overall survival. ASTCT consensus criteria are used to grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Responses are determined by Lugano 2014 (Cheson et al., JCO 2014).

Results: As of July 19, 2023, three patients were enrolled and all received treatment at DL1, 50x10 6 PMB-CT01(BAFFRCAR T cells). The median age was 56 years old (41-75), 100% male. Patients #1 and #2 had MCL and both had received prior treatment with BTK inhibitors, and progressed after CD19CAR T cell therapy. Both patients had bone marrow involvement prior to treatment, and had 4 and 10 prior lines of therapy, respectively. Patient #3 with T cell/histiocyte-rich B cell lymphoma had received 3 prior lines of therapy and his lymphoma was negative for both CD19 and CD20. All 3 patients developed grade 1 CRS only. All CRS events resolved with 2 doses of tocilizumab given to patient #1 and 1 dose to patient #2. Patients #1 and #2 also developed grade 1 ICANS which were self-limited and resolved without pharmacologic intervention. No dose-limiting toxicity (DLT) was observed. Infection was seen in patient #2 with viral pneumonia at month 3.

All 3 treated patients responded to treatment. The overall response rate was 100% including MRD-negative complete response (CR) by flow cytometry and next-generation sequencing (NGS) in patient #1 and by flow cytometry in patient #2, and partial response (PR) in patient #3. All responses are ongoing at 8 months (patient #1), 4 months (patient #2) and 1.5 months (patient #3), respectively. Figure 1 shows the clearance of lymphoma cells in the bone marrow of the first patient 28 days post- CAR T cell infusion. Robust CAR T cell expansion was observed in all 3 patients with peak of expansion (between 2.1x10 6 and 8.9x10 6 copies/ml of blood) on day 12 (patient #1) and day 14 (patients #2 and #3) (Figure 1).

Conclusions: PMB-CT01(BAFFRCART cell) treatment at DL1 was safe and demonstrated potent anti-lymphoma activity with a 100% ORR (2 CR, 1 PR) in patients with poor prognosis. CRS and ICANS were all grade 1 and reversible.Enrollment is ongoing at DL2, and additional clinical and correlative analyses will be presented at the meeting.