Please use this identifier to cite or link to this item: http://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
RMID: 0030023919
DOI: 10.1097/CJI.0000000000000061
Grant ID: http://purl.org/au-research/grants/nhmrc/1010386
Appears in Collections:Medicine publications

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