Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: results from a phase I clinical trial
Nathalie Asherie, Shlomit Kfir-Erenfeld, Batia Avni, Miri Assayag, Tatyana Dubnikov, Nomi Zalcman, Eyal Lebel, Eran Zimran, Adir Shaulov, Marjorie Pick, Yael Cohen, Irit Avivi, Cyrille Cohen, Moshe E Gatt, Sigal Grisariu, Polina Stepensky, Nathalie Asherie, Shlomit Kfir-Erenfeld, Batia Avni, Miri Assayag, Tatyana Dubnikov, Nomi Zalcman, Eyal Lebel, Eran Zimran, Adir Shaulov, Marjorie Pick, Yael Cohen, Irit Avivi, Cyrille Cohen, Moshe E Gatt, Sigal Grisariu, Polina Stepensky
Abstract
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.
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References
- Cowan AJ, Green DJ, Kwok M, et al. . Diagnosis and management of multiple myeloma: a review. JAMA. 2022;327(5):464-477.
- Gay F, Larocca A, Wijermans P, et al. . Complete response correlates with long-term progression free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood. 2011;117(11):3025-3031.
- Gandhi UH, Cornell RF, Lakshman A, et al. . Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275.
- Kumar SK, Dimopoulos MA, Kastritis E, et al. . Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443-2448.
- Pick M, Vainstein V, Goldschmidt N, et al. . Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol. 2018;100(5):494-501.
- Gill SK, Unawane R, Wang S, et al. . Inferior outcomes of patients with quad and penta-refractory multiple myeloma (MM) compared to those of patients who have been quad and penta exposed. Blood. 2021;138 (Supplement 1):4742.
- Vogl DT, Dingli D, Cornell RF, et al. . Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(9):859-866.
- Guo R, Lu W, Zhang Y, Cao X, Jin X, Zhao M. Targeting BCMA to treat multiple myeloma: updates from the 2021 ASH Annual Meeting. Front Immunol. 2022;13:839097.
- Munshi NC, Anderson LD Jr, Shah N, et al. . Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716.
- Berdeja JG, Madduri D, Usmani SZ, et al. . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324.
- Du J, Wei R, Jiang S, et al. . CAR-T cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status. Am J Hematol. 2022;97(7):933-941.
- Frigault MJ, Bishop MR, Rosenblatt J, et al. . Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv. 2023;7(5):768-777.
- Harush O, Asherie N, Kfir-Erenfeld S, et al. . Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma. Haematologica. 2022;107(10):2395-2407.
- Kumar S, Paiva B, Anderson KC, et al. . International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346.
- Theunissen P, Mejstrikova E, Sedek L, et al. . Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood. 2017;129(3):347-357.
- Lee DW, Santomasso BD, Locke FL, et al. . ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
- Laurent SA, Hoffmann FS, Kuhn PH, et al. . Gamma-secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6:7333.
- Ghermezi M, Li M, Vardanyan S, et al. . Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients. Haematologica. 2017;102(4):785-795.
- Raje N, Berdeja J, Lin Y, et al. . Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726-1737.
- Gazeau N, Beauvais D, Yakoub-Agha I, et al. . Effective anti-BCMA retreatment in multiple myeloma. Blood Adv. 2021;5(15):3016-3020.
- Mu W, Long X, Cai H, et al. . A model perspective explanation of the long-term sustainability of a fully human BCMA-targeting CAR (CT103A) T-cell immunotherapy. Front Pharmacol. 2022;13:803693.
- Cohen AD, Garfall AL, Dogan A, et al. . Serial treatment of relapsed/refractory multiple myeloma with different BCMA-targeting therapies. Blood Adv. 2019;3(16):2487-2490.
- Montes de Oca R, Alavi AS, Vitali N, et al. . Belantamab mafodotin (GSK2857916) drives immunogenic cell death and immune-mediated antitumor responses in vivo. Mol Cancer Ther. 2021;20(10):1941-1955.
- Carpenter RO, Evbuomwan MO, Pittaluga S, et al. . B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048-2060.
- Skerget M, Skopec B, Zadnik V, et al. . CD56 expression is an important prognostic factor in multiple myeloma even with bortezomib induction. Acta Haematol. 2018;139(4):228-234.
- Lebel E, Nachmias B, Pick M, Gross Even-Zohar N, Gatt ME. Understanding the bioactivity and prognostic implication of commonly used surface antigens in multiple myeloma. J Clin Med. 2022;11(7):1809.
- Pellat-Deceunynck C, Barille S, Jego G, et al. . The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma. Leukemia. 1998;12(12):1977-1982.
- Li G, Huang XJ, Niu T, et al. . [Expression of CD56 in multiple myeloma cells and its relationship with extramedullary disease and extramedullary relapse]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021;29(2):553-556.
- Chang H, Samiee S, Yi QL. Prognostic relevance of CD56 expression in multiple myeloma: a study including 107 cases treated with high-dose melphalan-based chemotherapy and autologous stem cell transplant. Leuk Lymphoma. 2006;47(1):43-47.
- Hayden PJ, Sirait T, Koster L, Snowden JA, Yakoub-Agha I. An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT. Curr Res Transl Med. 2019;67(3):79-88.
- Till BG, Jensen MC, Wang J, et al. . CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012;119(17):3940-3950.
- Prommersberger S, Reiser M, Beckmann J, et al. . CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Ther. 2021;28(9):560-571.
- Kebriaei P, Singh H, Huls MH, et al. . Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363-3376.
- Townsend MH, Bennion K, Robison RA, O'Neill KL. Paving the way towards universal treatment with allogenic T cells. Immunol Res. 2020;68(1):63-70.
Source: PubMed