Abstract
As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct “head-to-head” comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that “toggle” TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.
Highlights
Malignant GliomasWith an estimated incidence of 14.7 per 100,000 people in the United States and upward of 10,000–15,000 new annual cases, primary malignant tumors of the brain pose a formidable front in the world of oncology [1,2,3]
M032 has not been associated with adverse events in humans, given its limited use to date it is plausible that it might result in adverse events comparable to those observed in phase I trials of doubly mutant oHSV (G207), a genetically engineered herpes simplex virus (HSV)
Documented adverse effects related to administration of G207 included: headache, nausea, drowsiness, weakness, anemia, and leukopenia [Appendix D in Supplementary Material includes a list of adverse events and related international medical terminology (IMT) terms]
Summary
With an estimated incidence of 14.7 per 100,000 people in the United States and upward of 10,000–15,000 new annual cases, primary malignant tumors of the brain pose a formidable front in the world of oncology [1,2,3]. Malignant gliomas are the most prevalent primary brain tumors, accounting for ∼30% of all primary central nervous system (CNS) tumors in adults [4]. CNS tumors represent ∼25% of all childhood. Similar incidences of spontaneous central nervous system tumors have been observed in pet canines, at an estimated 14.5 per 100,000 animals [6]. With a tendency toward certain breeds, up to 35% of these tumors that manifest represent gliomas that clinically behave like malignant gliomas in humans and share similar radiographic, histopathologic, and genetic features with similar treatment and outcome patterns [7]. Result in disability, and lead to premature death
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