Oncolytic virus therapy is being evaluated in clinical trials for human
glioma. While it is widely assumed that the immune response of the patient to the
virus infection limits the utility of the
therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic
infection in
glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic
glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated
tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV
infection. To determine the role on the clinical utility of MYXV
therapy for
glioma, we used a combination of knockout mouse strains and specific immunocyte
ablation techniques. Collectively, our experiments identify an important role for
tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from
gliomas. Using a
cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the
tumor-resident macrophage population. Virotherapy of
cyclophosphamide-treated animals resulted in sustained
viral infection within the
glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic
glioma models involves a multifaceted cellular immune response that can be overcome with
cyclophosphamide-mediated lymphoablation.