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

Richard A. Morgan, Nachimuthu Chinnasamy, Daniel Abate-Daga, Alena Gros, Paul F. Robbins, Zhili Zheng, Mark E. Dudley, Steven A. Feldman, James C. Yang, Richard M. Sherry, Giao Q. Phan, Marybeth S. Hughes, Udai S. Kammula, Akemi D. Miller, Crystal J. Hessman, Ashley A. Stewart, Nicholas P. Restifo, Martha M. Quezado, Meghna Alimchandani, Avi Z. RosenbergAvindra Nath, Tongguang Wang, Bibiana Bielekova, Simone C. Wuest, Nirmala Akula, Francis J. McMahon, Susanne Wilde, Barbara Mosetter, Dolores J. Schendel, Carolyn M. Laurencot, Steven A. Rosenberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)133-151
Number of pages19
JournalJournal of Immunotherapy
Volume36
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • TCR
  • cancer-testes antigen
  • gene therapy
  • immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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