Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus

Abstract

Aim: To molecularly characterize the tumor microenvironment and evaluate immunologic parameters in canine glioma patients before and after treatment with oncolytic human IL-12-expressing herpes simplex virus (M032) and in treatment naïve canine gliomas. Methods: We assessed pet dogs with sporadically occurring gliomas enrolled in Stage 1 of a veterinary clinical trial that was designed to establish the safety of intratumoral oncoviral therapy with M032, a genetically modified oncolytic herpes simplex virus. Specimens from dogs in the trial and dogs not enrolled in the trial were evaluated with immunohistochemistry, NanoString, Luminex cytokine profiling, and multi-parameter flow cytometry. Results: Treatment-naive canine glioma microenvironment had enrichment of Iba1 positive macrophages and minimal numbers of T and B cells, consistent with previous studies identifying these tumors as immunologically “cold”. NanoString mRNA profiling revealed enrichment for tumor intrinsic pathways consistent with suppression of tumor-specific immunity and support of tumor progression. Oncolytic viral treatment induced an intratumoral mRNA transcription signature of tumor-specific immune responses in 83% (5/6) of canine glioma patients. Changes included mRNA signatures corresponding with interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. Multiplexed protein analysis identified a subset of oligodendroglioma subjects with increased concentrations of IL-2, IL-7, IL-6, IL-10, IL-15, TNFα, GM-CSF between 14 and 28 days after treatment, with evidence of CD4+ T cell activation and modulation of IL-4 and IFNγ production in CD4+ and CD8+ T cells isolated from peripheral blood. Conclusion: These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model.

Advancements in drug delivery methods for the treatment of brain disease

“…The utility of HSV-1 as a vector for CNS gene transfer has been previously demonstrated in the dog, as intracerebral injections of HSV-1 into normal dog brains did not result in any neuropathological lesions, latent viral DNA was detected in brain regions remote from the injection site, and human IL-12 will induce a systemic T-cell response in dogs (63,64). No significant adverse events attributable to administration of HSV-1 or dose-limiting toxicities were observed in this study, and molecular and genomic analyses of a subset of treated canine tumors revealed tumoral transcriptional and peripheral blood cytokine signatures of anti-tumor immune pathway activation including interferon signaling, lymphoid and myeloid cell activation, and T and B cell immunity (64,65).…”

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

“…Similarly, an oncolytic herpes virus was used for canine gliomas. Pre-treatment biopsy samples showed significant infiltration with macrophages, and transcriptome analysis indicated myeloid cell activation after treatment ( 172 ). A whole-cell autologous cancer vaccine for metastatic canine hemangiosarcoma utilized a protein immune adjuvant known to activate macrophages and other immune cells ( 309 , 310 ).…”

Oncolytic herpes simplex viruses for the treatment of glioma and targeting glioblastoma stem-like cells

“…While HSV-1 is not pathogenic in dogs, canine glioma cells are similarly susceptible to killing as mouse cells. M032 treatment induced transcriptional signatures of immune modulation, both inflammatory and immunosuppressive ( Chambers et al., 2021 ). For dogs with high-grade gliomas, the mean survival time after treatment was 108 days, and no significant adverse events were attributable to M032 ( Omar et al., 2021 ).…”