Stuck in traffic: CART cells targeting the tumor microenvironment in hematological malignancies, current advances and future perspectives.

Chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment of B cell hematological malignancies, and has lead to several FDA-approved CART products beginning in 2017. However, while CART cell therapy has improved outcomes and survival, many patients eventually relapse after treatment. Research into the reasons for patient relapse following CART cell therapy has identified multiple mechanisms of resistance. These primarily include antigen loss, poor CART cell expansion or exhaustion, and tumor- or tumor-microenvironment (TME)-mediated immunosuppression of CART cells. While methods to study and engineer CART cells to circumvent antigenic loss or to prevent exhaustion are being investigated, the development of standalone or combination CART cell therapies that target both cancer cells and immunosuppressive components of the TME are less studied. In this review, we focus on the impact of the TME on CART cell efficacy in hematological malignancies and discuss promising basic and clinical approaches that may enable CART cells to overcome TME-mediated dysfunction.