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Morgan, R.A.* ; Chinnasamy, N.* ; Abate-Daga, D.* ; Gros, A.* ; Robbins, P.F.* ; Zheng, Z.L.* ; Dudley, M.E.* ; Feldman, S.A.* ; Yang, J.C.* ; Sherry, R.M.* ; Phan, G.Q.* ; Hughes, M.S.* ; Kammula, U.S.* ; Miller, A.D.* ; Hessman, C.J.* ; Stewart, A.A.* ; Restifo, N.P.* ; Quezado, M.M.* ; Alimchandani, M.* ; Rosenberg, A.Z.* ; Nath, A.* ; Wang, T.G.* ; Bielekova, B.* ; Wuest, S.C.* ; Akula, N.* ; McMahon, F.J.* ; Wilde, S. ; Mosetter, B. ; Schendel, D.J. ; Laurencot, C.M.* ; Rosenberg, S.A.*

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

J. Immunother. 36, 133-151 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 leukoence-phalopathy 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 MAGEA9). 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cancer-testes Antigen ; Immunotherapy ; Tcr ; Gene Therapy; Inflammatory Demyelinating Polyneuropathy ; Adoptive Cell Therapy ; Cd8(+) T-cells ; Mage-a Family ; Metastatic Melanoma ; Multiple-sclerosis ; Cancer/testis Antigens ; Malignant-melanoma ; Prostate-cancer ; Clinical-trial
ISSN (print) / ISBN 1524-9557
e-ISSN 1537-4513
Journal Journal of Immunotherapy
Quellenangaben Volume: 36, Issue: 2, Pages: 133-151 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)