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221 Promising Safety and Anti-Lymphoma Efficacy of Autologous Pmb-CT01 (BAFFRCAR T Cell) Therapy in a First-in-Human Phase 1 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Expanding Disease Targets for CAR-T Cell Therapies
Hematology Disease Topics & Pathways:
clinical trials, adult, Biological therapies, Research, Lymphomas, non-Hodgkin lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, B Cell lymphoma, Clinical Research, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, Human, Study Population, Minimal Residual Disease
Saturday, December 9, 2023: 3:00 PM

Elizabeth Lihua Elizabeth Budde, MD, PhD1, Marissa Morales Del Real, PhD2*, John H. Baird, MD3, Lu Chen, PhD4*, Joo Y. Song, MD5, Swetha Kambhampati, MD3, Alan Macias2*, Teresa Kim6*, Sylvia Dulan6*, Baishakhi Barva, MBBS6*, Sandrine Puverel, PhD3*, Katrin Tiemann, PhD6*, Hazel Ting-Ying Cheng, PhD7*, Stephen J. Forman, MD, FACP3 and Larry W. Kwak, MD, PhD3

1Department of Hematology and HCT, City of Hope, Duarte, CA
2T-Cell Therapeutics Research Laboratories, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
3Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA
4Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA
5Beckman Research Institute, City of Hope, Duarte, CA
6City of Hope National Medical Center, Duarte, CA
7PeproMene Bio. Inc, Irvine, CA

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 study is a phase 1, single center, open label, therapeutic trial. PMB-CT01 is a TN/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 50x106 (DL1), 200x106 (DL2), and 600x106 (DL3) CAR T cells. The lymphodepletion regimen consists of cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/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, 50x106 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 2.1x106 and 8.9x106 copies/ml of blood) on day 12 (patient #1) and day 14 (patients #2 and #3) (Figure 1).

Conclusions: PMB-CT01(BAFFRCAR T 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.

Disclosures: Budde: Merck: Research Funding; Amgen: Research Funding; ADC Therapeutics: Consultancy; Roche: Consultancy; AstraZeneca: Consultancy, Research Funding; Novartis, Gilead, F. Hoffmann-La Roche Ltd, BeiGene, Genentech, Inc.: Consultancy; MustangBio: Research Funding. Baird: Genentech-Roche: Research Funding; Regeneron Pharmaceuticals: Research Funding; Kite Pharma-Gilead: Research Funding, Speakers Bureau; Cellular Biomedicine Group: Research Funding. Kambhampati: ADC Therapeutics: Research Funding; Genentech: Research Funding; Genmab: Research Funding. Cheng: PeproMene Bio. Inc: Current Employment. Kwak: PeproMene Bio. Inc: Consultancy, Current equity holder in private company.

*signifies non-member of ASH