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

Abstract

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 TCR engineered T cells. Five patients experienced clinical regression of their cancers including two on-going responders. Beginning 1–2 days post-infusion, three patients (#’s 5, 7, and 8) experienced mental status changes, and two 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 Q-RT-PCR, Nano string 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.

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

“…Indeed, engineered T-cells demonstrated higher affinity for the HLA-A*0201-restricted epitope K MA ELVHFL of MAGE-A12 than for the targeted K VA ELVHFL epitope of MAGE-A3. 40 Peptide #31 (used to re-stimulate PBMCs in our ELISpot) contained the sequence K VA ELVHFL. In our study, four primates had specific immune responses to the fully conserved peptide 31.…”

“…Transfusion of engineered anti-MAGE-A3 CD8 + T-cells resulted in clinical regressions of tumors, but this treatment was deemed unsafe due to the aforementioned neurotoxocity. 40 Anti-MAGE-A3 vaccination has also been evaluated clinically using a recombinant protein strategy and, although this treatment was safe, no survival advantage was conferred. However, the induction of T-cell responses was not reported, precluding full assessment of this platform’s immunogenicity.…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…Despite robust antitumor immunity using TCRs targeting diverse cancer antigens, there are severe unanticipated adverse effects resulting from T cell recognition of tissue-specific antigens gp100 and MART-1 expressed by both normal melanocytes and melanoma [203], or from the cross-reactivity of higher affinity MAGE-A3 TCR-transduced T cells against epitopes in unintended targets in normal and essential tissues [204,205]. Vaccination of cancer patients with gp100 and MART-1 resulted in objective clinical response without serious toxicity to melanocytes [182,185].…”

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma

“…For instance, the neurological toxicity of anti-MAGE-A3 TCR gene therapy (also recognizing MAGE-A9 and A12 epitopes) might be related to unreported MAGE-A12 expression in brain. 22 The uncertainty over antigen expression patterns in normal tissue implies a need for systematic monitoring of potential toxicity.…”