Details

Autor(en) / Beteiligte

• 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
• McMahon, Francis J
• Wilde, Susanne
• Mosetter, Barbara
• Schendel, Dolores J
• Laurencot, Carolyn M
• Rosenberg, Steven A

Titel

Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy

Ist Teil von

• Journal of immunotherapy (1997), 2013-02, Vol.36 (2), p.133

Ort / Verlag

United States

Erscheinungsjahr

2013

Link zum Volltext

Beschreibungen/Notizen

• 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.