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

被引：861

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
Alli, Rajshekhar
Phuong Nguyen
Geiger, Terrence L.
[J]. JOURNAL OF IMMUNOLOGY, 2011, 187 (11) : 5521 - 5531
[2] Evolution of the exon-intron structure and alternative splicing of the MAGE-A family of cancer/testis antigens
Artamonova, II
Gelfand, MS
[J]. JOURNAL OF MOLECULAR EVOLUTION, 2004, 59 (05) : 620 - 631
[3] Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming
Atanackovic, Djordje
Altorki, Nasser K.
Cao, Yanran
Ritter, Erika
Ferrara, Cathy A.
Ritter, Gerd
Hoffman, Eric W.
Bokemeyer, Carsten
Old, Lloyd J.
Gnjatic, Sacha
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (05) : 1650 - 1655
[4] High frequency of MAGE-A4 and MAGE-A9 expression in high-risk bladder cancer
Bergeron, Alain
Picard, Valerie
LaRue, Helene
Harel, Francois
Hovington, Helene
Lacombe, Louis
Fradet, Yves
[J]. INTERNATIONAL JOURNAL OF CANCER, 2009, 125 (06) : 1365 - 1371
[5] Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis
Bielekova, B
Catalfamo, M
Reichert-Scrivner, S
Packer, A
Cerna, M
Waldmann, TA
McFarland, H
Henkart, PA
Martin, R
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) : 5941 - 5946
[6] Chronic inflammatory demyelinating polyneuropathy associated with malignant melanoma
Bird, SJ
Brown, MJ
Shy, ME
Scherer, SS
[J]. NEUROLOGY, 1996, 46 (03) : 822 - 824
[7] Treatment of Chronic Lymphocytic Leukemia With Genetically Targeted Autologous T Cells: Case Report of an Unforeseen Adverse Event in a Phase I Clinical Trial
Brentjens, Renier
Yeh, Raymond
Bernal, Yvette
Riviere, Isabelle
Sadelain, Michel
[J]. MOLECULAR THERAPY, 2010, 18 (04) : 666 - 668
[8] Cancer immunotherapy targeting tumour-specific antigens: towards a new therapy for minimal residual disease
Brichard, Vincent G.
Lejeune, Diane
[J]. EXPERT OPINION ON BIOLOGICAL THERAPY, 2008, 8 (07) : 951 - 968
[9] GSK's antigen-specific cancer immunotherapy programme: Pilot results leading to Phase III clinical development
Brichard, Vincent G.
Lejeune, Diane
[J]. VACCINE, 2007, 25 : B61 - B71
[10] Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis
Brucklacher-Waldert, Verena
Sturner, Klarissa
Kolster, Manuela
Wolthausen, Julia
Tolosa, Eva
[J]. BRAIN, 2009, 132 : 3329 - 3341

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