Abstract 4568: The One Health Consortium and combination immunotherapy: evaluating M032, a genetically engineered HSV-1 expressing Il-12, in combination with a checkpoint inhibitor in canine glioma patients

Abstract

Abstract Introduction: Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary CNS tumors in adults (Levin et al., 2001). Interestingly, pet dogs spontaneously and sporadically develop malignant glial brain tumors that resemble high-grade gliomas in humans; with similar incidence, treatments, and outcome patterns. (Priester and McKay, 1980; Snyder et al., 2006; Ostrom et al., 2013; Ostrom et al., 2014; Hicks et al., 2017) The most malignant of these tumors have been refractory to limited treatment options. Despite aggressive treatment, outcomes are dismal with median survivals just over one year in humans and two months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. Background: This pre-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 is evaluating M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Note, prior studies have demonstrated human IL-12 to generate effective anti-tumoral response in canine patients (Pavlin et al., 2012). M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials are proceeding concurrently, allowing a direct “head-to-head” comparison of safety and efficacy. Methods: Stage 1 of the trial, which is presently ongoing, involves catheter-based administration of MO32 alone into the tumor resection cavity at escalating doses in subsequent cohorts of dogs to establish maximum tolerable dose (MTD), detect dose limiting toxicities (DLT), quantify immune response via serum assays, and determine survival benefit. Stage 2 will involve administration of a fixed dose of MO32 derived from Stage 1 data followed by 4 weeks of daily Indoximod administration at a pre-determined dose, with interval comparative immune assays, neurological monitoring, and imaging surveillance. Indoximod is expected to blunt suppressive cellular (Tregs, MDSCs) immune response components, allowing a longer time for effective anti-viral responses and via cross-epitope spreading, an anti-tumor response that will be more durable than that observed with administration of virus alone. In all cases, tumor is collected, processed, and archived for future studies, including whole genome and RNA sequencing. Results: Preliminary data from Stage 1 have demonstrated a median survival of 188 days among all canines following infusion of M032 HSV (95% confidence interval of 83.2 to 292.8 days). Nine canines have died and eight are still alive following treatment. Current dose is 1 x 109 plaque-forming units. No dose limiting toxicities have been observed with infusion of M032 alone. Conclusions: The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as a valid and informative model of human brain tumors. The results of this and subsequent studies will allow canine trials to properly inform the design of human trials and further support bi-translational studies and the One Medicine approach to clinical research and application. Citation Format: M. R. Chambers, R. T. Bentley, David Crossman, Jeremy B. Foote, J. W. Koehler, James M. Markert, Simon R. Platt, Nidal B. Omar, D. M. Self, Andy Shores, Don Sorjonen, Alicia M. Waters, Amy B. Yanke, G Y. Gillespie. The One Health Consortium and combination immunotherapy: evaluating M032, a genetically engineered HSV-1 expressing Il-12, in combination with a checkpoint inhibitor in canine glioma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4568.