Modifying interleukin-2 concentrations during culture improves function of T cells for adoptive immunotherapy

Background Adoptive immunotherapy with cytotoxic T cells has shown promising clinical results in patients with metastatic melanoma and post-transplant-associated viral infections. Cell transfer therapies often require the ex vivo expansion of large numbers of reactive lymphocytes. Therefore interleu...

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Bibliographic Details
Published in:Cytotherapy (Oxford, England) England), 2009-01, Vol.11 (2), p.206-217
Main Authors: Besser, M.J, Schallmach, E, Oved, K, Treves, A.J, Markel, G, Reiter, Y, Schachter, J
Format: Article
Language:English
Subjects:
adoptive immunotherapies
Advanced Basic Science
Antigens, Differentiation - biosynthesis
Antigens, Neoplasm - metabolism
Cell Proliferation
Coculture Techniques
Culture Media
Cytotoxicity, Immunologic
ex vivo expansion
Humans
Immunotherapy, Adoptive
Interferon-gamma - secretion
interleukin-2
Interleukin-2 - immunology
Interleukin-2 - metabolism
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Lymphocytes, Tumor-Infiltrating - pathology
Melanoma - immunology
Melanoma - metabolism
Melanoma - pathology
Neoplasm Metastasis
Other
T cell
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
T-Lymphocytes, Cytotoxic - pathology
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Summary:Background Adoptive immunotherapy with cytotoxic T cells has shown promising clinical results in patients with metastatic melanoma and post-transplant-associated viral infections. Cell transfer therapies often require the ex vivo expansion of large numbers of reactive lymphocytes. Therefore interleukin-2 (IL-2), a potent T-cell mitogenic cytokine that critically affects the features and effectiveness of T cells, is frequently added to cell culture media. Methods We examined the influence of various IL-2 concentrations on cell growth, cytotoxicity, cytokine release and surface marker expression of tumor-infiltrating lymphocytes (TIL) during a standard 14-day rapid expansion phase. The study was conducted under good manufacturing practice (GMP) conditions, using approved reagents in a class 10000 laboratory. Results T-cell cultures grown in very high IL-2 concentrations (600–6000 IU/mL) expanded massively and maximally secreted interferon (IFN)-γ in response to antigenic stimulation, but exhibited only low direct cytotoxicity. On the other hand, TIL cultures grown in low concentrations of IL-2 throughout the rapid expansion phase expanded to a lower extent and barely secreted IFN-γ but displayed high cytotoxic activity. A combined approach of starting with 10–120 IU/mL IL-2 during the first week, followed by increasing the IL-2 concentration to 6000 IU/mL during the second week, results in T cells that expand well, maximally produce IFN-γ and are highly cytotoxic against tumor cells. Discussion Fine tuning of the IL-2 concentration during ex vivo expansion of T cells can yield high numbers of T cells with optimal features for clinical use.
ISSN:1465-3249
1477-2566
DOI:10.1080/14653240802590391