This study reports the clinical application of MAGE-A3 TCR gene-modified T cells in nine cancer patients, including five with metastatic melanoma, one with synovial sarcoma, and one with esophageal cancer. Five patients experienced clinical regression of their cancers, including two ongoing responders. However, three patients developed severe neurologic toxicity, with two lapsing into comas and dying. Brain imaging and autopsy revealed periventricular leukomalacia and necrotizing leukoencephalopathy with extensive white matter defects associated with CD3+/CD8+ T cell infiltration. The MAGE-A3 TCR used in this study recognized epitopes in MAGE-A3/A9/A12, and molecular assays indicated that MAGE-A12 was expressed in human brain. This previously unrecognized expression of MAGE-A12 may have initiated a TCR-mediated inflammatory response that led to neuronal cell destruction, raising caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.This study reports the clinical application of MAGE-A3 TCR gene-modified T cells in nine cancer patients, including five with metastatic melanoma, one with synovial sarcoma, and one with esophageal cancer. Five patients experienced clinical regression of their cancers, including two ongoing responders. However, three patients developed severe neurologic toxicity, with two lapsing into comas and dying. Brain imaging and autopsy revealed periventricular leukomalacia and necrotizing leukoencephalopathy with extensive white matter defects associated with CD3+/CD8+ T cell infiltration. The MAGE-A3 TCR used in this study recognized epitopes in MAGE-A3/A9/A12, and molecular assays indicated that MAGE-A12 was expressed in human brain. This previously unrecognized expression of MAGE-A12 may have initiated a TCR-mediated inflammatory response that led to neuronal cell destruction, raising caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.