A major limiting factor in the success of CAR T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues, which poses significant risks to patients. We found that CAR T cells against GD2, a tumor-associated antigen highly expressed in neuroblastoma, induced rapid, fatal neurotoxicity due to CAR recognition of GD2 positive normal mouse brain tissue. To improve selectivity of the CAR T cell for the cancer only, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to a cell adhesion target upregulated in solid tumor neovasculature with minimal expression in normal brain and peripheral nerve tissue. These tumor microenvironment actuated T cells restricted expression of the GD2 CAR to tumor tissue, preventing fatal neurotoxicity while maintaining anti-tumor efficacy. We also found that conditional CAR expression improved CAR T cell anti-tumor efficacy by improving metabolic fitness and maintaining a less differentiated memory phenotype. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and killing to malignant tissue only and provides a proof-of-concept model for other difficult solid tumor targets.