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Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy
Open accessAbstract
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.
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Metadata
- Authors
- Morgan, R. A., Chinnasamy, N., Abate-Daga, D., Gros, A., Robbins, P. F., Zheng, Z., 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., Bielekova, B., Wuest, S. C., Akula, N., McMahon, F. J., Wilde, S., Mosetter, B., Schendel, D. J., Laurencot, C. M., & Rosenberg, S. A.
- Venue
- Journal of Immunotherapy
- Published
- 2013-02
- Volume
- 36
- Issue
- 2
- Pages
- 133-151
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W2070748533
- Cited by
- 1,148
- References
- 8
- FWCI
- 46.64
- Type
- journal article
- Language
- en
- Open access
- green
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- Morgan, R. A., Chinnasamy, N., Abate-Daga, D., Gros, A., Robbins, P. F., Zheng, Z., 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, S. A. (2013). Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy. Journal of Immunotherapy. https://doi.org/10.1097/cji.0b013e3182829903
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
