title: Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.
abstract: Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.
authors: Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA. rmorgan@mail.nih.gov
authors: Richard A
authors: RA
authors: Morgan
authors: Nachimuthu
authors: N
authors: Chinnasamy
authors: Daniel
authors: D
authors: Abate-Daga
authors: Alena
authors: A
authors: Gros
authors: Paul F
authors: PF
authors: Robbins
authors: Zhili
authors: Z
authors: Zheng
authors: Mark E
authors: ME
authors: Dudley
authors: Steven A
authors: SA
authors: Feldman
authors: James C
authors: JC
authors: Yang
authors: Richard M
authors: RM
authors: Sherry
authors: Giao Q
authors: GQ
authors: Phan
authors: Marybeth S
authors: MS
authors: Hughes
authors: Udai S
authors: US
authors: Kammula
authors: Akemi D
authors: AD
authors: Miller
authors: Crystal J
authors: CJ
authors: Hessman
authors: Ashley A
authors: AA
authors: Stewart
authors: Nicholas P
authors: NP
authors: Restifo
authors: Martha M
authors: MM
authors: Quezado
authors: Meghna
authors: M
authors: Alimchandani
authors: Avi Z
authors: AZ
authors: Rosenberg
authors: Avindra
authors: A
authors: Nath
authors: Tongguang
authors: T
authors: Wang
authors: Bibiana
authors: B
authors: Bielekova
authors: Simone C
authors: SC
authors: Wuest
authors: Nirmala
authors: N
authors: Akula
authors: Francis J
authors: FJ
authors: McMahon
authors: Susanne
authors: S
authors: Wilde
authors: Barbara
authors: B
authors: Mosetter
authors: Dolores J
authors: DJ
authors: Schendel
authors: Carolyn M
authors: CM
authors: Laurencot
authors: Steven A
authors: SA
authors: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D022223:Vaccines, Subunit / Q000276:immunology; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; C505356:MAGE-9 antigen, human; C409589:MAGEA12 protein, human; C072013:MAGEA3 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit
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