| Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy. | |
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MedLine Citation:
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PMID: 23377668 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2013-1-30 |
Journal Detail:
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Title: Journal of immunotherapy (Hagerstown, Md. : 1997) Volume: - ISSN: 1537-4513 ISO Abbreviation: J. Immunother. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-2-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9706083 Medline TA: J Immunother Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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*Surgery Branch †Laboratory of Pathology, National Cancer Institute ‡Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke §Human Genetics Branch, National Institute of Mental Health, Bethesda, MD ∥Institute of Molecular Immunology ¶Clinical Cooperation Group "Immune Monitoring," Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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