TGFB1 and neoplasm: Additional methods to improve CAR T cell persistence and reduce functional exhaustion currently under development in preclinical models include the use of fully humanized variable chains to reduce immunogenicity and rejection of cells containing the CAR construct (67–70), combination costimulation with novel signaling pathways such as ICOS (71), cytokine manipulation to promote T cell activation and epitope spreading (72), combination therapy with immunomodulatory agents such as lenalidomide (73, 74), and blocking TGF-β responsiveness to inhibit tumor-induced immunosuppression (75).