Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy.
Morgan, Richard A. *; Chinnasamy, Nachimuthu *; Abate-Daga, Daniel *; Gros, Alena *; Robbins, Paul F. *; Zheng, Zhili *; Dudley, Mark E. *; Feldman, Steven A. *; Yang, James C. *; Sherry, Richard M. *; Phan, Giao Q. *; Hughes, Marybeth S. *; Kammula, Udai S. *; Miller, Akemi D. *; Hessman, Crystal J. *; Stewart, Ashley A. *; Restifo, Nicholas P. *; Quezado, Martha M. +; Alimchandani, Meghna +; Rosenberg, Avi Z. +; Nath, Avindra ++; Wang, Tongguang ++; Bielekova, Bibiana ++; Wuest, Simone C. ++; Akula, Nirmala [S]; McMahon, Francis J. [S]; Wilde, Susanne [//]; Mosetter, Barbara [//]; Schendel, Dolores J. [//],[P]; Laurencot, Carolyn M. *; Rosenberg, Steven A. *
Journal of Immunotherapy.
36(2):133-151, February-March 2013.
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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.
(C) 2013 Lippincott Williams & Wilkins, Inc.