Open AccessEvaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus
Author(s) -
M. R. Chambers,
Jeremy B. Foote,
R. Timothy Bentley,
D. Botta,
David K. Crossman,
Debbie L. Della Manna,
Dagoberto Estévez-Ordoñez,
J. W. Koehler,
Catherine P. Langford,
Margaret A. Miller,
James M. Markert,
Alicia K. Olivier,
Nidal B. Omar,
Simon Platt,
Daniel R. Rissi,
Andy Shores,
Donald C. Sorjonen,
Erwan Yang,
Amy B. Yanke,
G. Yancey Gillespie
Publication year - 2021
Language(s) - English
DOI - 10.20517/jtgg.2021.31
Subject(s) - oncolytic virus , glioma , tumor microenvironment , immune system , herpes simplex virus , cd8 , immunotherapy , medicine , cancer research , cytokine , flow cytometry , immunology , biology , virus
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.