Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy

被引：885

作者：

Morgan, Richard A. ^{[1
]}

Chinnasamy, Nachimuthu ^{[1
]}

Abate-Daga, Daniel ^{[1
]}

Gros, Alena ^{[1
]}

Robbins, Paul F. ^{[1
]}

Zheng, Zhili ^{[1
]}

Dudley, Mark E. ^{[1
]}

Feldman, Steven A. ^{[1
]}

Yang, James C. ^{[1
]}

Sherry, Richard M. ^{[1
]}

Phan, Giao Q. ^{[1
]}

Hughes, Marybeth S. ^{[1
]}

Kammula, Udai S. ^{[1
]}

Miller, Akemi D. ^{[1
]}

Hessman, Crystal J. ^{[1
]}

Stewart, Ashley A. ^{[1
]}

Restifo, Nicholas P. ^{[1
]}

Quezado, Martha M. ^{[2
]}

Alimchandani, Meghna ^{[2
]}

Rosenberg, Avi Z. ^{[2
]}

Nath, Avindra ^{[3
]}

Wang, Tongguang ^{[3
]}

Bielekova, Bibiana ^{[3
]}

Wuest, Simone C. ^{[3
]}

Akula, Nirmala ^{[4
]}

McMahon, Francis J. ^{[4
]}

Wilde, Susanne ^{[5
]}

Mosetter, Barbara ^{[5
]}

Schendel, Dolores J. ^{[5
,6
]}

Laurencot, Carolyn M. ^{[1
]}

Rosenberg, Steven A. ^{[1
]}

机构：

[1] NCI, Surg Branch, Bethesda, MD 20892 USA

[2] NCI, Pathol Lab, Bethesda, MD 20892 USA

[3] NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA

[4] NIMH, Human Genet Branch, Bethesda, MD 20892 USA

[5] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Mol Immunol, Munich, Germany

[6] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Clin Cooperat Grp Immune Monitoring, Munich, Germany

来源：

JOURNAL OF IMMUNOTHERAPY | 2013年 / 36卷 / 02期

关键词：

cancer-testes antigen; immunotherapy; TCR; gene therapy; INFLAMMATORY DEMYELINATING POLYNEUROPATHY; MAGE-A FAMILY; METASTATIC MELANOMA; CANCER/TESTIS ANTIGENS; PROSTATE-CANCER; ADVERSE EVENT; HIGH AVIDITY; CELLS; EXPRESSION; TARGETS;

D O I：

10.1097/CJI.0b013e3182829903

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：133 / 151

页数：19

共 71 条

[1] Altered Differentiation, Diminished Pathogenicity, and Regulatory Activity of Myelin-Specific T Cells Expressing an Enhanced Affinity TCR [J].