Document Detail

Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.
MedLine Citation:
PMID:  23377668     Owner:  NLM     Status:  MEDLINE    
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.
Richard A Morgan; Nachimuthu Chinnasamy; Daniel Abate-Daga; Alena Gros; Paul F Robbins; Zhili Zheng; Mark E Dudley; Steven A Feldman; James C Yang; Richard M Sherry; Giao Q Phan; Marybeth S Hughes; Udai S Kammula; Akemi D Miller; Crystal J Hessman; Ashley A Stewart; Nicholas P Restifo; Martha M Quezado; Meghna Alimchandani; Avi Z Rosenberg; Avindra Nath; Tongguang Wang; Bibiana Bielekova; Simone C Wuest; Nirmala Akula; Francis J McMahon; Susanne Wilde; Barbara Mosetter; Dolores J Schendel; Carolyn M Laurencot; Steven A Rosenberg
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, N.I.H., Intramural    
Journal Detail:
Title:  Journal of immunotherapy (Hagerstown, Md. : 1997)     Volume:  36     ISSN:  1537-4513     ISO Abbreviation:  J. Immunother.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-08     Completed Date:  2013-07-23     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9706083     Medline TA:  J Immunother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  133-51     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
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MeSH Terms
Antigens, Neoplasm* / genetics,  immunology,  therapeutic use
Brain / metabolism
Dendritic Cells / immunology
Gene Transfer Techniques
Genetic Therapy / methods*
Immunotherapy, Adoptive* / adverse effects,  methods,  mortality
Melanoma / immunology,  therapy*
Melanoma-Specific Antigens
Middle Aged
Neoplasm Proteins* / genetics,  immunology,  therapeutic use
RNA, Messenger / analysis
Receptors, Antigen, T-Cell* / genetics,  immunology,  therapeutic use
Vaccines, Subunit / immunology
Young Adult
Grant Support
Reg. No./Substance:
0/Antigens, Neoplasm; 0/MAGE-9 antigen, human; 0/MAGEA12 protein, human; 0/MAGEA3 protein, human; 0/Melanoma-Specific Antigens; 0/Neoplasm Proteins; 0/RNA, Messenger; 0/Receptors, Antigen, T-Cell; 0/Vaccines, Subunit
Comment In:
J Immunother. 2013 Feb;36(2):79-81   [PMID:  23377666 ]

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