CAR T cells, CAR NK cells, and CAR macrophages exhibit distinct traits in glioma models but are similarly enhanced when combined with cytokines
Thomas Look, Roman Sankowski, Manon Bouzereau, Serena Fazio, Miaomiao Sun, Alicia Buck, Niklas Binder, Max Mastall, Francesco Prisco, Frauke Seehusen, Julia Frei, C. Wyss, Berend Snijder, César Nombela Arrieta, Michael Weller, Steve Pascolo, Tobias Weiß
Abstract
Chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy against cancer. Although there is a growing interest in other cell types, a comparison of CAR immune effector cells in challenging solid tumor contexts is lacking. Here, we compare mouse and human NKG2D-CAR-expressing T cells, natural killer (NK) cells, and macrophages against glioblastoma, the most aggressive primary brain tumor. In vitro we show that T cell cancer killing is CAR dependent, whereas intrinsic cytotoxicity overrules CAR dependence for NK cells, and CAR macrophages reduce glioma cells in co-culture assays. In orthotopic immunocompetent glioma mouse models, systemically administered CAR T cells demonstrate superior accumulation in the tumor, and each immune cell type induces distinct changes in the tumor microenvironment. An otherwise low therapeutic efficacy is significantly enhanced by co-expression of pro-inflammatory cytokines in all CAR immune effector cells, underscoring the necessity for multifaceted cell engineering strategies to overcome the immunosuppressive solid tumor microenvironment. • CAR T cells, CAR NK cells, and CAR macrophages can be efficiently generated with mRNA • The CAR effector cells exhibit different anti-tumor activities in glioma mouse models • Each CAR immune cell type has a distinct effect on the tumor microenvironment • Co-expression of cytokines increases the anti-tumor potential of CAR immune cells This comparative analysis of CAR T cells, CAR NK cells, and CAR macrophages in glioma mouse models by Look et al. reveals distinct features for each cell type, emphasizes the benefit of combinatorial approaches such as the co-expression of cytokines, and sets the groundwork for future developments.