Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy Journal Article

Authors: Hollyman, D.; Stefanski, J.; Przybylowski, M.; Bartido, S.; Borquez-Ojeda, O.; Taylor, C.; Yeh, R.; Capacio, V.; Olszewska, M.; Hosey, J.; Sadelain, M.; Brentjens, R. J.; Riviere, I.
Article Title: Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy
Abstract: On the basis of promising preclinical data demonstrating the eradication of systemic B-cell malignancies by CD19-targeted T lymphocytes in vivo in severe combined immunodeficient-beige mouse models, we are launching phase I clinical trials in patients with chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia. We present here the validation of the bioprocess which we developed for the production and expansion of clinical grade autologous T cells derived from patients with CLL. We demonstrate that T cells genetically modified with a replication-defective gammaretroviral vector derived from the Moloney murine leukemia virus encoding a chimeric antigen receptor (CAR) targeted to CD19 (1928z) can be expanded with Dynabeads CD3/CD28. This bioprocess allows us to generate clinical doses of 1928z T cells in approximately 2 to 3 weeks in a large-scale semiclosed culture system using the Wave Bioreactor. These 1928z T cells remain biologically functional not only in vitro but also in severe combined immunodeficient-beige mice bearing disseminated tumors. The validation requirements in terms of T-cell expansion, T-cell transduction with the 1928z CAR, biologic activity, quality control testing, and release criteria were met for all 4 validation runs using apheresis products from patients with CLL. Additionally, after expansion of the T cells, the diversity of the skewed Vβ T-cell receptor repertoire was significantly restored. This validated process will be used in phase I clinical trials in patients with chemorefractory CLL and in patients with relapsed acute lymphoblastic leukemia. It can also be adapted for other clinical trials involving the expansion and transduction of patient or donor T cells using any CAR or T-cell receptor. © 2009 by Lippincott Williams & Wilkins.
Keywords: controlled study; human cell; genetics; clinical trial; nonhuman; clinical trials as topic; t lymphocyte; quality control; mouse; animal; animals; mice; animal experiment; animal model; validation study; transplantation; acute lymphoblastic leukemia; genetic transduction; transduction, genetic; t lymphocyte receptor beta chain; immunology; dna modification; biological activity; genetic engineering; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; retrovirus vector; cell culture techniques; chimeric antigen receptor; cell therapy; adoptive transfer; culture technique; chronic lymphatic leukemia; moloney leukemia oncovirus; validation; adoptive immunotherapy; cell expansion; immunotherapy, adoptive; autologous t cells; biologic activity in vitro and in vivo; bioreactor; dynabeads cd3/cd28; gammaretroviral vector; large-scale expansion; phase i clinical trial; cd19 antigen; lymphocyte antigen receptor; burkitt lymphoma; scid mouse; antigens, cd19; bioreactors; leukemia, lymphocytic, chronic, b-cell; receptors, antigen
Journal Title: Journal of Immunotherapy
Volume: 32
Issue: 2
ISSN: 1524-9557
Publisher: Lippincott Williams & Wilkins  
Date Published: 2009-02-01
Start Page: 169
End Page: 180
Language: English
DOI: 10.1097/CJI.0b013e318194a6e8
PUBMED: 19238016
PROVIDER: scopus
PMCID: PMC2683970
Notes: --- - "Cited By (since 1996): 16" - "Export Date: 30 November 2010" - "CODEN: JOIME" - "Source: Scopus"
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