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https://hdl.handle.net/2440/99369
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Type: | Journal article |
Title: | BRAF and MEK inhibition variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro |
Author: | Gargett, T. Fraser, C. Dotti, G. Yvon, E. Brown, M. |
Citation: | Journal of Immunotherapy, 2015; 38(1):12-23 |
Publisher: | Lippincott Williams & Wilkins |
Issue Date: | 2015 |
ISSN: | 1524-9557 1537-4513 |
Statement of Responsibility: | Tessa gargett. Cara K. Fraser, Gianpietro Dotti, Eric S. Yvon, Michael Brown |
Abstract: | Cancer immunotherapy has long been used in the treatment of metastatic melanoma, and an anti-CTLA-4 monoclonal antibody treatment has recently been approved by the US Food and Drug Administration. Targeted therapies such as small molecule kinase inhibitors targeting deregulated mitogen-activated protein kinase (MAPK) signaling have markedly improved melanoma control in up to 50% of metastatic disease patients and have likewise been recently approved. Combination therapies for melanoma have been proposed as a way to exploit the high-level but short-term responses associated with kinase inhibitor therapies and the low-level but longer-term responses associated with immunotherapy. Cancer immunotherapy now includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells and this mode of therapy is a candidate for combination with small molecule drugs. This paper describes CART cells that target GD2-expressing melanoma cells and investigates the effects of approved MAPK pathway-targeted therapies for melanoma [vemurafenib (Vem), dabrafenib (Dab), and trametinib (Tram)] on the viability, activation, proliferation, and cytotoxic T lymphocyte activity of these CAR T cells, as well as on normal peripheral blood mononuclear cells. We report that, although all these drugs lead to inhibition of stimulated T cells at high concentrations in vitro, only Vem inhibited T cells at concentrations equivalent to reported plasma concentrations in treated patients. Although the combination of Dab and Tram also resulted in inhibition of T-cell effector functions at some therapeutic concentrations, Dab itself had little adverse effect on CAR T-cell function. These findings may have implications for novel therapeutic combinations of adoptive CAR T-cell immunotherapy and MAPK pathway inhibitors. |
Keywords: | Leukocytes |
Rights: | © 2015 by Lippincott Williams & Wilkins |
DOI: | 10.1097/CJI.0000000000000061 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1010386 |
Published version: | http://dx.doi.org/10.1097/cji.0000000000000061 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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