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.
Highlights
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
These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model
Microvascular density was assessed in the canine glioma tumor microenvironment (TME) using immunohistochemistry for FVIIIrelated antigen
Summary
Glioma is the most prevalent primary brain tumor in humans, accounting for approximately 30% of adults’ primary central nervous system tumors[1,2]. The molecular signatures of human glioma have been characterized by sequencing techniques. They are being used to individualize treatments, and some biomarkers, such as IDH mutation, 1p19q codeletion, MGMT promoter methylation, and EGFR vIII amplification, may be of prognostic value[1,2]. While the expanded use of whole-genome sequencing and targeted therapies have offered improved outcomes to some, the prognosis for the most malignant of these tumors remains dismal, with a median survival of approximately 17 months from diagnosis[4]. Advancements in brain tumor therapies have come slowly, and a comparative oncologic approach and modeling of immunotherapies offer great promise, with noted advantages and limitations[5]
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