title: BRAF and MEK inhibition variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro.
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.
authors.affiliation: *Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, and University of South Australia §Cancer Clinical Trials Unit, Royal Adelaide Hospital ∥Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia †Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital ‡Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gargett
authors.forename: Cara K
authors.initials: CK
authors.lastname: Fraser
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Eric S
authors.initials: ES
authors.lastname: Yvon
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000276:immunology*; D010091:Oximes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013449:Sulfonamides / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic; D014162:Transfection; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011948:Receptors, Antigen, T-Cell; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib