Myxoma Virus Oncolysis of Primary and Metastatic B16F10 Mouse Tumors In Vivo

Abstract

Myxoma virus (MV) is a rabbit-specific poxvirus, whose unexpected tropism to human cancer cells has led to studies exploring its potential use in oncolytic therapy. MV infects a wide range of human cancer cells in vitro, in a manner intricately linked to the cellular activation of Akt kinase. MV has also been successfully used for treating human glioma xenografts in immunodeficient mice. This study examines the effectiveness of MV in treating primary and metastatic mouse tumors in immunocompetent C57BL6 mice. We have found that several mouse tumor cell lines, including B16 melanomas, are permissive to MV infection. B16F10 cells were used for assessing MV replication and efficacy in syngeneic primary tumor and metastatic models in vivo. Multiple intratumoral injections of MV resulted in dramatic inhibition of tumor growth. Systemic administration of MV in a lung metastasis model with B16F10LacZ cells was dramatically effective in reducing lung tumor burden. Combination therapy of MV with rapamycin reduced both size and number of lung metastases, and also reduced the induced antiviral neutralizing antibody titres, but did not affect tumor tropism. These results show MV to be a promising virotherapeutic agent in immunocompetent animal tumor models, with good efficacy in combination with rapamycin.

Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide

“…Improved results have also been seen in immunocompetent animals using an oncolytic herpes virus in combination with the cyclophosphamide to suppress the immune response and provide for prolonged replication of the virus (25,26). Recently, we and others have shown that the combination of myxoma virus plus rapamycin led to enhanced viral replication in vitro and in vivo, and improved efficacy against medulloblastomas (27) and melanoma (28). This led us to investigate the use of oncolytic vaccinia virus in combination with rapamycin or cyclophosphamide therapy for the treatment of experimental models of malignant gliomas.…”

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

“…2). Although rapamycin in conjunction with other viruses (e.g., myxoma virus, vaccinia virus, or adenovirus) augment oncolysis (23,(33)(34)(35)(36), the molecular mechanism by which this process occurs remained elusive. Autophagy and the antiangiogenic effect induced by rapamycin were postulated to promote viral oncolysis (35,37).…”

Myxoma Virus Virotherapy for Glioma in Immunocompetent Animal Models: Optimizing Administration Routes and Synergy with Rapamycin

“…Few have used immunocompetent models (23)(24)(25)(26). We have reported promising efficacy of MYXV in immunocompromised brain tumor models (5,14,15); there is one report of MYXV in an immunocompetent model of melanoma (16). The evaluation of an oncolytic virus in immunocompetent setting is important because both the innate and the acquired immune system may dramatically modulate oncolytic efficacy.…”

“…We discovered that myxoma virus (MYXV) was oncolytic for several human cancers (5,(13)(14)(15)(16). It is promising for human therapy because its genome has been sequenced, it is simple to engineer, its natural tropism is highly restricted to European rabbits (Oryctolagus cuniculus), and there is no acquired viral immunity in humans (17).…”

“…In our study, we chose rapamycin as a cotherapeutic with MYXV for several reasons. First, rapamycin enhances MYXV tumor cell infection in vitro [possibly by further activating Akt (30) or inhibiting a type I IFN response (31)] and in animal tumor models (14,16). Second, rapamycin is a potent immunosuppressant that inhibits the development and/or activation of numerous arms of the innate or adaptive immune response, most well studied being the blocking of T-cell activation/proliferation during allograft rejection (32).…”