Spatial Control ofCAR T Cell Activation Using Tumor-HomingPolymers

CAR T cell therapies often lack specificity, leading to issues ranging from inadequate antigen targeting to off-tumor toxicities. To counter that lack of specificity, we expanded tumor targeting capabilities with universal CAR and spatially defined CAR T cell engagement with targets through a combination of synthetic biology and biomaterial approaches. We developed a novel framework, called “<i>In situ</i> Mobilization: Polymer Activated Cell Therapies” (IMPACT) for polymer-mediated, anatomical control of IF-THEN gated CAR T cells. With IMPACT, a regulated payload such as a BiTE or tumor-targeting CAR will only be expressed after engineered cells engage a tumor-localizing polymer (“IF” condition). In this first demonstration of IMPACT, we engineered CAR T cells to respond to fluorescein that is displayed by an injectable polymer that binds to and is retained in fibrin deposits in tumor microenvironments. This interaction then drives selective and conditional expression of a protein within tumors (“THEN” condition). Here, we develop the polymer and CAR T cell infrastructure of IMPACT and demonstrate tumor-localized CAR T cell activation in a murine tumor model after the intravenous administration of polymer and engineered T cells.