IFNg is Critical for CAR T Cell Mediated Myeloid Activation and Induction of Endogenous Immunity.

Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity, however, their indirect effects on the endogenous immune system is not well characterized. Remarkably, we demonstrate that CAR T cell treatment of mouse syngeneic glioblastoma activates intratumoral myeloid cells and induces endogenous T cell memory responses coupled with feed-forward propagation of CAR T responses. IFNy production by CAR T cells and IFNy-responsiveness of host immune cells is critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these observations is supported by studies showing that human IL13Ra2-CAR T cells activate patient-derived endogenous T cells and monocyte/macrophages through IFNy-signaling, as well as induce the generation of tumor-specific T cell responses in a responding patient with GBM. These studies establish that CAR T therapy has the potential to shape the tumor microenvironment, creating a context permissible for eliciting endogenous antitumor immunity.