The One Health Consortium: Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Combination With a Checkpoint Inhibitor in Canine Patients With Sporadic High Grade Gliomas

Abstract

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.

Safety and interim survival data after intracranial administration of M032, a genetically engineered oncolytic HSV-1 expressing IL-12, in pet dogs with sporadic gliomas

“…The viral dose was determined via the previously published dose escalation scheme in subsequent cohorts of dogs (Tables 1 and 2). 9 A protocolized schedule of inpatient and subsequent outpatient clinical, radiographic, and laboratory surveillance for adverse effects and dose-limiting toxicities has been previously described through a period of 12 months following treatment (Table 3). 9 Histological diagnoses of oligodendroglioma, astrocy-toma, or undefined glioma and assignment of low or high grade were made by the participating veterinary pathologists and based on the NCI Comparative Brain Tumor Consortium (CBTC) Pathology Board criteria.…”

“…9 A protocolized schedule of inpatient and subsequent outpatient clinical, radiographic, and laboratory surveillance for adverse effects and dose-limiting toxicities has been previously described through a period of 12 months following treatment (Table 3). 9 Histological diagnoses of oligodendroglioma, astrocy-toma, or undefined glioma and assignment of low or high grade were made by the participating veterinary pathologists and based on the NCI Comparative Brain Tumor Consortium (CBTC) Pathology Board criteria. 16 Basic descriptive statistics including mean and standard deviation were calculated using the Microsoft Excel (2007) functions "AVERAGE" and "STDEV," respectively.…”

“…The authors have previously published background work and the design of an ongoing phase I clinical trial, known as "CANINE," studying the use of a genetically engineered herpesvirus with or without an immune checkpoint inhibitor in pet dogs with sporadic gliomas. 9 M032 is an oncolytic herpes simplex virus-1 (HSV-1) vector with deletion of its neurovirulent γ 34.5 subunit, further engineered to express human interleukin-12 (IL-12). 10 Human IL-12 has previously been shown in veterinary studies to induce a systemic T-cell response in dogs.…”

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

“…The oHSV M032, the human-IL-12-expressing version of M002, has been tested for safety and stability in non-human primates by intracerebral administration [71,84]. At present, a phase I clinical trial with M032 is recruiting patients with recurrent/progressive GBM, anaplastic astrocytoma, or gliosarcoma, with an estimated study completion date of September 2023 (NCT02062827), and phase I trials on animals have been designed [85]. A multipronged engineering strategy with immunostimulatory genes has been assayed too-the combined administration of three oHSVs armed with different cytokines (IL-12, IL-18) or soluble CD80 (B7-1) showed a greater oncolytic effect relative to the administration of the same cumulative dose of just a single type of armed oHSV [86].…”

“…RP1, a GALV fusogenic protein, and GM-CSF armed oHSV are presently being assayed with nivolumab (anti-PD-1) in solid tumors (NCT03767348) [177]. A phase I trial on canine patients with IL-12-expressing M032 oHSV in combination with a checkpoint inhibitor has been designed [85]. In a preclinical setting of a more "cold", non-immunogenic tumor, such as GBM, G47∆ showed the best efficacy when in "triple combination", i.e., administered simultaneously with both anti-PD-1 and anti-CTLA-4 antibodies, with up to 89% long-term survivors, the establishment of immunological memory, and the lack of recurrence of the tumor [100,178,179].…”