Abstract
Chimeric antigen receptor (CAR) T cells face a unique set of challenges in the context of solid tumors. To induce a favorable clinical outcome, CAR T cells have to surmount a series of increasingly arduous tasks. First, they have to be made specific for an antigen whose expression clearly demarcates tumor from normal tissue. Then, they must be able to home and penetrate the desmoplastic stroma that surrounds the tumor. Once within the tumor, they must expand, persist, and mediate cytotoxicity in a hostile milieu largely composed of immunosuppressive modulators. Whereas a seemingly herculean task, all of the aforementioned requirements can potentially be met effectively through both intrinsic and/or extrinsic modifications of CAR T cells. In this review, we delineate the barriers imposed by solid tumors on CARs and strategies that have and should be undertaken to improve therapeutic response.