Cancer regression and neurologic toxicity following anti-MAGE-A3 TCR gene therapy
By R. Morgan, N. Chinnasamy, Daniel Abate-Daga, A. Gros, P. Robbins, Zhili Zheng, S. Feldman, Jie Yang, R. Sherry, G. Phan and 20 more. Journal of immunotherapy, 2013
1,094 citations recorded by the source corpus.
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.
Subfields: Immunology, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/7aa2687c12cb4a7c5d7e1948df72adad364e4e95
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Citations in the corpus
- The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “At autopsy, extensive necrotizing leukoencephalopathy associated with T cell infiltration was observed (Morgan et al., 2013).”
- Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, neutral): “This toxicity has not been documented in clinical trials ofCARs, but it has been observed in clinical trials of T cells genetically modified to express T-cell receptors.(33,52,53)”
- Precision Tumor Recognition by T Cells With Combinatorial Antigen Sensing Circuits (2016, positive): “Although patients can live without B cells, this type of treatment would be far more broadly applicable if T cell therapeutics could more reliably discriminate normal tissue from diseased (Lamers et al., 2006; Morgan et al., 2013; 2010; Sadelain et al., 2009).”
- Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. (2013, background): “MAGE-A3 may be a particularly difficult target because another group using an independently derived TCR that was specific for MAGE-A3 peptides presented on HLAA*02 has reported severe on-target off-tumor toxicity.(25) In that study, neurologic toxicity was observed because of the unexpected expressi”
- A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: Long term follow up and correlates with response (2014, background): “The toxicity appeared to result from cross-reactivity of TCR-transduced T cells with a nearly identical epitope fromMAGE-A12, a protein that was found to be expressed at low levels in normal brain tissue (23).”