Point-Of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-automatic Bioreactor: Experience From an Academic Phase I Clinical Trial
Por:
Castella M, Caballero-Baños M, Ortiz-Maldonado V, González-Navarro EA, Suñé G, Antoñana-Vidósola A, Boronat A, Marzal B, Millán L, Martín-Antonio B, Jordi Cid Colom, Lozano M, García E, Tabera J, Trias E, Perpiña U, Canals JM, Baumann T, Benítez-Ribas D, ELENA CAMPO, Yagüe-Ribes J, Urbano-Ispizua Á, Rives-Solà S, Delgado J and Juan-Otero M
Publicada:
20 mar 2020
Ahead of Print:
20 mar 2020
Resumen:
Development of semi-automated devices that can reduce the hands-on time and standardize the production of clinical-grade CAR T-cells, such as CliniMACS Prodigy from Miltenyi, is key to facilitate the development of CAR T-cell therapies, especially in academic institutions. However, the feasibility of manufacturing CAR T-cell products from heavily pre-treated patients with this system has not been demonstrated yet. Here we report and characterize the production of 28 CAR T-cell products in the context of a phase I clinical trial for CD19+ B-cell malignancies (NCT03144583). The system includes CD4-CD8 cell selection, lentiviral transduction and T-cell expansion using IL-7/IL-15. Twenty-seven out of 28 CAR T-cell products manufactured met the full list of specifications and were considered valid products. Ex vivo cell expansion lasted an average of 8.5 days and had a mean transduction rate of 30.6 +/- 13.44%. All products obtained presented cytotoxic activity against CD19+ cells and were proficient in the secretion of pro-inflammatory cytokines. Expansion kinetics was slower in patient's cells compared to healthy donor's cells. However, product potency was comparable. CAR T-cell subset phenotype was highly variable among patients and largely determined by the initial product. T-CM and T-EM were the predominant T-cell phenotypes obtained. 38.7% of CAR T-cells obtained presented a T-N or T-CM phenotype, in average, which are the subsets capable of establishing a long-lasting T-cell memory in patients. An in-depth analysis to identify individual factors contributing to the optimal T-cell phenotype revealed that ex vivo cell expansion leads to reduced numbers of T-N, T-SCM, and T-EFF cells, while T-CM cells increase, both due to cell expansion and CAR-expression. Overall, our results show for the first time that clinical-grade production of CAR T-cells for heavily pre-treated patients using CliniMACS Prodigy system is feasible, and that the obtained products meet the current quality standards of the field. Reduced ex vivo expansion may yield CAR T-cell products with increased persistence in vivo.
Filiaciones:
Castella M:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Blood and Tissue Bank (BST), Barcelona, Spain
Caballero-Baños M:
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Hospital Sant Joan de Déu, Barcelona, Spain
Ortiz-Maldonado V:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
González-Navarro EA:
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Suñé G:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Antoñana-Vidósola A:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Boronat A:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Marzal B:
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Millán L:
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Martín-Antonio B:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Jordi Cid Colom:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Hemotherapy and Hemostasis, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Lozano M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Hemotherapy and Hemostasis, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
García E:
Blood and Tissue Bank (BST), Barcelona, Spain
Apheresis Unit, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
Tabera J:
Blood and Tissue Bank (BST), Barcelona, Spain
Unit of Advanced Therapies, Hospital Clínic de Barcelona, Barcelona, Spain
Trias E:
Unit of Advanced Therapies, Hospital Clínic de Barcelona, Barcelona, Spain
Perpiña U:
Stem Cells and Regenerative Medicine Laboratory, Department of Biomedical Sciences, Production and Validation Center of Advanced Therapies (Creatio), Universitat de Barcelona, Barcelona, Spain
Canals JM:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Stem Cells and Regenerative Medicine Laboratory, Department of Biomedical Sciences, Production and Validation Center of Advanced Therapies (Creatio), Universitat de Barcelona, Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Baumann T:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Benítez-Ribas D:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
ELENA CAMPO:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Department of Pathology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain
Centro de Investigación Biomedical en Red de Cancer, Barcelona, Spain
Instituciò Catalana de Recerca i Estudis Avancats, Barcelona, Spain
Yagüe-Ribes J:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Urbano-Ispizua Á:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Department of Biomedicine, School of Medicine, Josep Carreras Leukemia Research Institute, Universitat de Barcelona, Barcelona, Spain
Immunotherapy Unit Blood and Tissue Bank-Hospital Clínic de Barcelona, Barcelona, Spain
Rives-Solà S:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Delgado J:
Department of Hematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic de Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomedical en Red de Cancer, Barcelona, Spain
Juan-Otero M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Blood and Tissue Bank (BST), Barcelona, Spain
Department of Immunology, Centro de Diagnóstico Biomédico, Hospital Clínic de Barcelona, Barcelona, Spain
Hospital Sant Joan de Déu, Barcelona, Spain
Universitat de Barcelona, Barcelona, Spain
Immunotherapy Unit Blood and Tissue Bank-Hospital Clínic de Barcelona, Barcelona, Spain
Green Submitted, gold
|