Point-of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-automatic Bioreactor: Experience From an Academic Phase I Clinical Trial
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 o...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repositorio: | Docusalut |
| Idioma: | inglés |
| OAI Identifier: | oai:docusalut.com:20.500.13003/19751 |
| Acceso en línea: | https://hdl.handle.net/20.500.13003/19751 |
| Access Level: | acceso abierto |
| Palabra clave: | Child Young Adult Cytotoxicity, Immunologic Point-of-Care Systems Adult Humans Adolescent Cells, Cultured Academic Medical Centers Cell Proliferation Automation Immunologic Memory Male T-Lymphocytes Immunotherapy, Adoptive Female Bioreactors Reactores Biológicos Proliferación Celular Linfocitos T Femenino Inmunoterapia Adoptiva Memoria Inmunológica Adolescente Masculino Automatización Sistemas de Atención de Punto Centros Médicos Académicos Humanos Adulto Joven Células Cultivadas Niño Citotoxicidad Inmunológica Adulto chimeric antigen receptor CD19 leukemia lymphoma immunotherapy CAR T-cell production CliniMACS Prodigy |
| Sumario: | 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. |
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