TY - JOUR
T1 - Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy
AU - Morgan, Richard A.
AU - Chinnasamy, Nachimuthu
AU - Abate-Daga, Daniel
AU - Gros, Alena
AU - Robbins, Paul F.
AU - Zheng, Zhili
AU - Dudley, Mark E.
AU - Feldman, Steven A.
AU - Yang, James C.
AU - Sherry, Richard M.
AU - Phan, Giao Q.
AU - Hughes, Marybeth S.
AU - Kammula, Udai S.
AU - Miller, Akemi D.
AU - Hessman, Crystal J.
AU - Stewart, Ashley A.
AU - Restifo, Nicholas P.
AU - Quezado, Martha M.
AU - Alimchandani, Meghna
AU - Rosenberg, Avi Z.
AU - Nath, Avindra
AU - Wang, Tongguang
AU - Bielekova, Bibiana
AU - Wuest, Simone C.
AU - Akula, Nirmala
AU - McMahon, Francis J.
AU - Wilde, Susanne
AU - Mosetter, Barbara
AU - Schendel, Dolores J.
AU - Laurencot, Carolyn M.
AU - Rosenberg, Steven A.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - TCR
KW - cancer-testes antigen
KW - gene therapy
KW - immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=84873991752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873991752&partnerID=8YFLogxK
U2 - 10.1097/CJI.0b013e3182829903
DO - 10.1097/CJI.0b013e3182829903
M3 - Article
C2 - 23377668
AN - SCOPUS:84873991752
SN - 1524-9557
VL - 36
SP - 133
EP - 151
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 2
ER -