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

Toews, K.; Grunewald, L.; Schwiebert, S.; Klaus, A.; Winkler, A.; Ali, S.; Zirngibl, F.; Astrahantseff, K.; Wagner, D.L.; Henssen, A.G.; Deubzer, H.E.; Schulte, J.H.; Ochsenreither, S.; Eggert, A.; Künkele, A.

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., Grunewald, L., Schwiebert, S., Klaus, A., Winkler, A., Ali, S., Zirngibl, F., Astrahantseff, K., Wagner, D.L., Henssen, A.G., Deubzer, H.E., Schulte, J.H., Ochsenreither, S., 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
ISSN:	0899-1987
Publisher:	Wiley
Volume:	59
Number:	7
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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