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

doi:10.3324/haematol.2022.281628

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^*

^*Corresponding author for this work

Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 27^th (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.

Original language	American English
Pages (from-to)	1827-1839
Number of pages	13
Journal	Haematologica
Volume	108
Issue number	7
DOIs	https://doi.org/10.3324/haematol.2022.281628
State	Published - Jul 2023

Bibliographical note

Funding Information:
We would like to thank the patients and their families for participating in the study. We would also like to express our gratitude to the management of Hadassah Medical Center for their ongoing support and their deep commitment to innovation. We also thank the staff in the clinical units for patient care, Mrs. Avigail Avraham from the apheresis unit, Mrs. Nassreen Hussein for cell manufacturing, and Mrs. Gili Gruzman for QC testing and patient follow-up. We are extremely grateful for the generous support for this clinical research under the leadership of Prof. Polina Stepensky, by The Manfred Steinfeld Family and The Estate of Allan Habelson. We gratefully acknowledge the support of the Amyloidosis Patient Association of Israel. CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20).

Funding Information:
CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20).

Publisher Copyright:
©2023 Ferrata Storti Foundation Published under a CC BY-NC license.

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10.3324/haematol.2022.281628

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Asherie, N., Kfir-Erenfeld, S., Avni, B., Assayag, M., Dubnikov, T., Zalcman, N., Lebel, E., Zimran, E., Shaulov, A., Pick, M., Cohen, Y., Avivi, I., Cohen, C., Gatt, M. E., Grisariu, S., & Stepensky, P. (2023). 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. Haematologica, 108(7), 1827-1839. https://doi.org/10.3324/haematol.2022.281628

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title = "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",

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.",

author = "Nathalie Asherie and Shlomit Kfir-Erenfeld and Batia Avni and Miri Assayag and Tatyana Dubnikov and Nomi Zalcman and Eyal Lebel and Eran Zimran and Adir Shaulov and Marjorie Pick and Yael Cohen and Irit Avivi and Cyrille Cohen and Gatt, {Moshe E.} and Sigal Grisariu and Polina Stepensky",

note = "Funding Information: We would like to thank the patients and their families for participating in the study. We would also like to express our gratitude to the management of Hadassah Medical Center for their ongoing support and their deep commitment to innovation. We also thank the staff in the clinical units for patient care, Mrs. Avigail Avraham from the apheresis unit, Mrs. Nassreen Hussein for cell manufacturing, and Mrs. Gili Gruzman for QC testing and patient follow-up. We are extremely grateful for the generous support for this clinical research under the leadership of Prof. Polina Stepensky, by The Manfred Steinfeld Family and The Estate of Allan Habelson. We gratefully acknowledge the support of the Amyloidosis Patient Association of Israel. CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20). Funding Information: CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20). Publisher Copyright: {\textcopyright}2023 Ferrata Storti Foundation Published under a CC BY-NC license.",

year = "2023",

month = jul,

doi = "10.3324/haematol.2022.281628",

language = "American English",

volume = "108",

pages = "1827--1839",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "7",

}

Asherie, N, Kfir-Erenfeld, S, Avni, B, Assayag, M, Dubnikov, T, Zalcman, N, Lebel, E, Zimran, E, Shaulov, A, Pick, M, Cohen, Y, Avivi, I, Cohen, C, Gatt, ME, Grisariu, S & Stepensky, P 2023, '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', Haematologica, vol. 108, no. 7, pp. 1827-1839. https://doi.org/10.3324/haematol.2022.281628

TY - JOUR

T1 - Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma

T2 - results from a phase I clinical trial

AU - Asherie, Nathalie

AU - Kfir-Erenfeld, Shlomit

AU - Avni, Batia

AU - Assayag, Miri

AU - Dubnikov, Tatyana

AU - Zalcman, Nomi

AU - Lebel, Eyal

AU - Zimran, Eran

AU - Shaulov, Adir

AU - Pick, Marjorie

AU - Cohen, Yael

AU - Avivi, Irit

AU - Cohen, Cyrille

AU - Gatt, Moshe E.

AU - Grisariu, Sigal

AU - Stepensky, Polina

N1 - Funding Information: We would like to thank the patients and their families for participating in the study. We would also like to express our gratitude to the management of Hadassah Medical Center for their ongoing support and their deep commitment to innovation. We also thank the staff in the clinical units for patient care, Mrs. Avigail Avraham from the apheresis unit, Mrs. Nassreen Hussein for cell manufacturing, and Mrs. Gili Gruzman for QC testing and patient follow-up. We are extremely grateful for the generous support for this clinical research under the leadership of Prof. Polina Stepensky, by The Manfred Steinfeld Family and The Estate of Allan Habelson. We gratefully acknowledge the support of the Amyloidosis Patient Association of Israel. CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20). Funding Information: CJC is supported by the Adelis Foundation and the Israel Science Foundation (646/20). Publisher Copyright: ©2023 Ferrata Storti Foundation Published under a CC BY-NC license.

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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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SN - 0390-6078

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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

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