58. Oncolytic Measles Virus Delivery by Infected Cell Carriers–A Strategy To “By-Pass” the Pre-Existing Humoral Immune Response

Abstract

Attenuated measles virus (MV) propagates selectively in human tumor cells and phase I clinical trials are currently underway to test their oncolytic activity. However, rapid antibody-mediated neutralization of the therapeutic viruses in blood or peritoneal fluid poses a major threat to the success of the approach. Classical and alternative complement pathway activation also contributes to complete virus neutralization in the plasma. Viremia during natural measles infection is exclusively cell-associated such that live MV can be isolated only from infected PBMC and not as cell-free virions from serum samples. We therefore hypothesized that autologous measles infected cells might be a more reliable vehicle than cell free virions to deliver the infection to tumor cells in subjects with neutralizing titers of anti-measles antibodies. Our in vitro studies, using a dual color fluorescent model, demonstrated the efficiency of cell-to-cell transfer of infection. In contrast to naked virions, heterofusion between infected monocytic line and tumor cells was 16-32 times more resistant to antibody neutralization. Systemically and intraperitoneally (i.p.) administered infected monocytes or stimulated peripheral blood cells successfully delivered oncolytic MV to the tumor lesions. Repeated i.p. injections of cell carriers significantly improved survival in an ovarian cancer xenograft model. MV survived antibody and complement neutralization within infected cells. In contrast to the naked virus, cell delivered MV and heterofusion escaped from the neutralizing antibodies after systemic or i.p. injection in a lymphoma metastatic model, and an i.p. hepatocellular cancer model. In addition, we demonstrated antibody-enhanced infectivity in monocytes/macrophages and subsequent transfer of MV infection to the target cells. These results suggest a novel strategy for systemic delivery of oncolytic virotherapy in cancer patients that can “by-pass” the pre-existing humoral immunity against MV. Attenuated measles virus (MV) propagates selectively in human tumor cells and phase I clinical trials are currently underway to test their oncolytic activity. However, rapid antibody-mediated neutralization of the therapeutic viruses in blood or peritoneal fluid poses a major threat to the success of the approach. Classical and alternative complement pathway activation also contributes to complete virus neutralization in the plasma. Viremia during natural measles infection is exclusively cell-associated such that live MV can be isolated only from infected PBMC and not as cell-free virions from serum samples. We therefore hypothesized that autologous measles infected cells might be a more reliable vehicle than cell free virions to deliver the infection to tumor cells in subjects with neutralizing titers of anti-measles antibodies. Our in vitro studies, using a dual color fluorescent model, demonstrated the efficiency of cell-to-cell transfer of infection. In contrast to naked virions, heterofusion between infected monocytic line and tumor cells was 16-32 times more resistant to antibody neutralization. Systemically and intraperitoneally (i.p.) administered infected monocytes or stimulated peripheral blood cells successfully delivered oncolytic MV to the tumor lesions. Repeated i.p. injections of cell carriers significantly improved survival in an ovarian cancer xenograft model. MV survived antibody and complement neutralization within infected cells. In contrast to the naked virus, cell delivered MV and heterofusion escaped from the neutralizing antibodies after systemic or i.p. injection in a lymphoma metastatic model, and an i.p. hepatocellular cancer model. In addition, we demonstrated antibody-enhanced infectivity in monocytes/macrophages and subsequent transfer of MV infection to the target cells. These results suggest a novel strategy for systemic delivery of oncolytic virotherapy in cancer patients that can “by-pass” the pre-existing humoral immunity against MV.