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| Home > Articles > Published articles > Point-of-care CAR T-cell production (ARI-0001) using a closed semi-automatic bioreactor : |
(Hospital Clínic i Provincial de Barcelona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Hospital Clínic i Provincial de Barcelona) (Universitat de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Hospital Clínic i Provincial de Barcelona) (Institució Catalana de Recerca i Estudis Avançats) (Universitat de Barcelona) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Hospital Clínic i Provincial de Barcelona)| Date: | 2020 |
| Abstract: | 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 and T were the predominant T-cell phenotypes obtained. 38. 7% of CAR T-cells obtained presented a TN or T 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, T, and T cells, while T 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. |
| Grants: | Instituto de Salud Carlos III PI13-00676 Instituto de Salud Carlos III PIE13-00033 Instituto de Salud Carlos III PI17-01043 Instituto de Salud Carlos III PICIS14-00122 Instituto de Salud Carlos III PI18-00775 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Chimeric antigen receptor ; CD19 ; Leukemia ; Lymphoma ; Immunotherapy ; CAR T-cell production ; CliniMACS Prodigy |
| Published in: | Frontiers in immunology, Vol. 11 (2020) , p. 482, ISSN 1664-3224 |
