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Haematologica. 2020 Jan 9. pii: haematol.2019.228577. doi: 10.3324/haematol.2019.228577. [Epub ahead of print]

Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma.

Author information

1
Department of Hematology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
2
Dept. of Pediatrics - Research, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
3
Lab. of Protein Design and Immunoengineering, Ecole Polytechnique Federale de Lausanne, Switzerland.
4
Department of Biosciences, U Science Tech. Universitat de Vic-Universitat Central de Catalunya,Spain.
5
Department of Immunology and Immunotherapy, Clinic Universitary of Navarra, Spain.
6
Josep Carreras Leukemia Research Institute/ Cell Therapy Program of the School of Medicine,Barcelona.
7
Department of Immunotherapy, Hospital Clinic, IDIBAPS, Barcelona, Spain.
8
Hospital Clinic, IDIBAPS,Josep Carreras Leukaemia Research Institute, University of Barcelona, Spain.
9
Hospital Clinic, IDIBAPS, Josep Carreras Leukaemia Research Institute, Barcelona, Spain bmartina@clinic.cat.

Abstract

Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in the treatment of patients with relapsed or refractory hematological B cell malignancies. In the recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immuno-therapy treatments including CART cells, for MM patients. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an at-tempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells demonstrated comparable in vitro and in vivo efficacy to ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells showed a lower TNFα production and lower in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrate that soluble BCMA and BCMA released in vesicles impacts on CAR-BCMA activity. In sum-mary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h cell treatment for multiple myeloma patients.

KEYWORDS:

BCMA; CART cell; Cell Therapy and Immunotherapy; Multiple Myeloma

PMID:
31919085
DOI:
10.3324/haematol.2019.228577
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