Nine patients received adoptive cell therapy with anti-MAGE-A3 TCR gene-modified T cells. Five patients experienced cancer regression, including two ongoing responders. Three patients (5, 7, and 8) showed mental status changes, and two (5 and 8) developed comas and died. MRI and autopsy revealed periventricular leukomalacia and necrotizing leukoencephalopathy with CD3+/CD8+ T cell infiltration. Patient 7 developed Parkinson-like symptoms that resolved. Immunohistochemical staining showed rare MAGE-A family-positive neurons. Molecular assays indicated MAGE-A12 expression in human brain. This expression may have triggered TCR-mediated inflammation, causing neuronal damage. The study highlights the risk of neurotoxicity in MAGE-A family-targeted therapies. The TCR recognized MAGE-A3/A9/A12 epitopes. Clinical trials showed tumor regression in some patients but also severe neurological toxicity. The TCR did not show off-target reactivity against non-MAGE-A genes. MAGE-A genes, including MAGE-A12, are expressed in human brain, raising concerns about targeting these antigens with active immunotherapies. The study underscores the need for caution in clinical applications targeting MAGE-A family members.Nine patients received adoptive cell therapy with anti-MAGE-A3 TCR gene-modified T cells. Five patients experienced cancer regression, including two ongoing responders. Three patients (5, 7, and 8) showed mental status changes, and two (5 and 8) developed comas and died. MRI and autopsy revealed periventricular leukomalacia and necrotizing leukoencephalopathy with CD3+/CD8+ T cell infiltration. Patient 7 developed Parkinson-like symptoms that resolved. Immunohistochemical staining showed rare MAGE-A family-positive neurons. Molecular assays indicated MAGE-A12 expression in human brain. This expression may have triggered TCR-mediated inflammation, causing neuronal damage. The study highlights the risk of neurotoxicity in MAGE-A family-targeted therapies. The TCR recognized MAGE-A3/A9/A12 epitopes. Clinical trials showed tumor regression in some patients but also severe neurological toxicity. The TCR did not show off-target reactivity against non-MAGE-A genes. MAGE-A genes, including MAGE-A12, are expressed in human brain, raising concerns about targeting these antigens with active immunotherapies. The study underscores the need for caution in clinical applications targeting MAGE-A family members.