482. T Cells as Carriers for Systemic Measles Virotherapy of Multiple Myeloma
Authors: Hooi T. Ong, Kosei Hasegawa, Mary Harvey, Allan Dietz, Stephen J. Russell, Kah-Whye Peng
Journal: Molecular Therapy (2006)

The bane of virotherapy is the presence of pre-existing antiviral antibodies or the induction of such antibodies after first dose therapy, which potentially could diminish therapeutic efficacy. We are interested to use oncolytic measles virus as a virotherapy agent for multiple myeloma, a disseminated plasma cell malignancy found predominantly in the bone marrow. Though about 50% of myeloma patients do not have protective levels of anti-measles antibodies due to their disease, we are keen to explore strategies to improve virus delivery to the tumor sites for patients that are positive for measles antibodies. Here, we investigated the potential of peripheral blood lymphocytes (PBLs) as carriers to protect and deliver oncolytic measles virus (MV) to myeloma cells and tumor xenografts in the presence and absence of neutralizing anti-measles antibodies. In contrast to cell-free virus, MV-infected PBLs were able to fuse with and transfer MV infection to myeloma cells after exposure to anti- measles antibodies. SCID mice bearing subcutaneous ARH-77 or disseminated KAS 6/1 myeloma xenografts were rendered measlesimmune by passive transfer of anti-measles antibodies. The biodistribution and pharmacokinetics of viral gene expression were monitored using luciferase imaging and tumor response followed via a soluble tumor marker. Gamma camera images using indium-111 oxine and fluorescence microscopy revealed that the majority of infected PBLs trafficked initially to the lungs and later to the liver, spleen and bone marrow. Imaging of virally encoded luciferase gene expression revealed intense signals in the lungs 30 min post cell infusion and subsequent trafficking of MV-Luc infected PBLs to tumor sites in measles naïve or immunized mice. Mice with subcutaneous tumors responded equally well to therapy by cell- free and cell-associated virus. Preliminary results with an advanced model of systemic myeloma disease showed no appreciable difference in therapeutic outcome with cell free or cell associated viruses. Oncolytic MV was delivered to tumor sites in the cell carrriers in the presence of anti-viral antibodies but subsequent virus spread was inhibited. It is likely that depletion of antiviral antibodies will be required for effective measles virotherapy in cancers where patients are not immunosuppressed with low Ab titers. The bane of virotherapy is the presence of pre-existing antiviral antibodies or the induction of such antibodies after first dose therapy, which potentially could diminish therapeutic efficacy. We are interested to use oncolytic measles virus as a virotherapy agent for multiple myeloma, a disseminated plasma cell malignancy found predominantly in the bone marrow. Though about 50% of myeloma patients do not have protective levels of anti-measles antibodies due to their disease, we are keen to explore strategies to improve virus delivery to the tumor sites for patients that are positive for measles antibodies. Here, we investigated the potential of peripheral blood lymphocytes (PBLs) as carriers to protect and deliver oncolytic measles virus (MV) to myeloma cells and tumor xenografts in the presence and absence of neutralizing anti-measles antibodies. In contrast to cell-free virus, MV-infected PBLs were able to fuse with and transfer MV infection to myeloma cells after exposure to anti- measles antibodies. SCID mice bearing subcutaneous ARH-77 or disseminated KAS 6/1 myeloma xenografts were rendered measlesimmune by passive transfer of anti-measles antibodies. The biodistribution and pharmacokinetics of viral gene expression were monitored using luciferase imaging and tumor response followed via a soluble tumor marker. Gamma camera images using indium-111 oxine and fluorescence microscopy revealed that the majority of infected PBLs trafficked initially to the lungs and later to the liver, spleen and bone marrow. Imaging of virally encoded luciferase gene expression revealed intense signals in the lungs 30 min post cell infusion and subsequent trafficking of MV-Luc infected PBLs to tumor sites in measles naïve or immunized mice. Mice with subcutaneous tumors responded equally well to therapy by cell- free and cell-associated virus. Preliminary results with an advanced model of systemic myeloma disease showed no appreciable difference in therapeutic outcome with cell free or cell associated viruses. Oncolytic MV was delivered to tumor sites in the cell carrriers in the presence of anti-viral antibodies but subsequent virus spread was inhibited. It is likely that depletion of antiviral antibodies will be required for effective measles virotherapy in cancers where patients are not immunosuppressed with low Ab titers.