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Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells

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Item Type:Article
Title:Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells
Creators Name:Toews, K. and Grunewald, L. and Schwiebert, S. and Klaus, A. and Winkler, A. and Ali, S. and Zirngibl, F. and Astrahantseff, K. and Wagner, D.L. and Henssen, A.G. and Deubzer, H.E. and Schulte, J.H. and Ochsenreither, S. and Eggert, A. and Künkele, A.
Abstract:The immunosuppressive microenvironment in solid tumors is thought to form a barrier to the entry and efficacy of cell-based therapies such as chimeric antigen receptor (CAR) T cells. Combining CAR T cell therapy with checkpoint inhibitors has been demonstrated to oppose immune escape mechanisms in solid tumors and augment antitumor efficacy. We evaluated PD-1/PD-L1 signaling capacity and the impact of an inhibitor of this checkpoint axis in an in vitro system for cancer cell challenge, the coculture of L1CAM-specific CAR T cells with neuroblastoma cell lines. Fluorescence-activated cell sorting-based analyses and luciferase reporter assays were used to assess PD-1/PD-L1 expression on CAR T and tumor cells as well as CAR T cell ability to kill neuroblastoma cells. Coculturing neuroblastoma cell lines with L1CAM-CAR T cells upregulated PD-L1 expression on neuroblastoma cells, confirming adaptive immune resistance. Exposure to neuroblastoma cells also upregulated the expression of the PD-1/PD-L1 axis in CAR T cells. The checkpoint inhibitor, nivolumab, enhanced L1CAM-CAR T cell-directed killing. However, nivolumab-enhanced L1CAM-CAR T cell killing did not strictly correlate with PD-L1 expression on neuroblastoma cells. In fact, checkpoint inhibitor success relied on strong PD-1/PD-L1 axis expression in the CAR T cells, which in turn depended on costimulatory domains within the CAR construct, and more importantly, on the subset of T cells selected for CAR T cell generation. Thus, T cell subset selection for CAR T cell generation and CAR T cell prescreening for PD-1/PD-L1 expression could help determine when combination therapy with checkpoint inhibitors could improve treatment efficacy.
Keywords:Central Memory T Cells, Chimeric Antigen Receptor T Cell Therapy, Microenvironment, PD‐1, PD‐L1
Source:Molecular Carcinogenesis
Page Range:724-273
Date:July 2020
Official Publication:https://doi.org/10.1002/mc.23202
PubMed:View item in PubMed

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