Infected Cell Carriers: A New Strategy for Systemic Delivery of Oncolytic Measles Viruses in Cancer Virotherapy

Abstract

Attenuated measles viruses (MVs) propagate selectively in human tumor cells, and phase I clinical trials are currently underway to test their oncolytic activity. A major theoretical impediment to systemic MV application is the presence of pre-existing antiviral immunity. We hypothesized that autologous MV-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 efficient cell-to-cell transfer of infection via heterofusion. In contrast to infection by naked virions, heterofusion between infected cell carriers and tumor cells was more resistant to antibody neutralization. Infected monocytic, endothelial, or stimulated peripheral blood cells could deliver oncolytic MV to tumor lesions in vivo, after intravenous (i.v.) or intraperitoneal (i.p.) administration. Single or repeated i.p. injections of monocytic carriers significantly improved survival of animals bearing human ovarian cancer xenografts. Systemic or i.p. injection of MV-infected cells successfully transferred infection by heterofusion to Raji lymphomas or hepatocellular carcinoma tumors in the presence of neutralizing antibodies. These results suggest a novel strategy for systemic delivery of oncolytic virotherapy in cancer patients that can "bypass" the pre-existing humoral immunity against MV.

Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth

“…An assortment of cells have been explored in this regard, including tumor cells, [49][50][51][52] outgrowth endothelial cells, 53 mesenchymal progenitor cells, 54,55 T cells 56,57 and monocytes. 58 There are several criteria that need to be addressed when determining which cell type should be utilized as a carrier for the delivery of a given oncolytic virus: (i) susceptibility to oncolytic virus infection, (ii) protection of the cargo from antibody neutralization, (iii) homing to sites of tumor growth and (iv) transfer of virus progeny to tumor tissue.…”

“…Recently, we illustrated that a monocytic cell line infected with MV could 'bypass' the inhibitory effects of MV antibodies and deliver MV to sites of tumor growth. 58 Macrophages are monocyte-derived cells that are often found in abundance in tumors and can be categorized as either M1 or M2 subtypes. 65 M1 macrophages suppress tumor growth, while M2 macrophages promote tumor growth.…”

Potential of tumour cells for delivering oncolytic viruses

“…On the other hand, cells derived from haematological malignancies are likely to be suitable for transferring OV to certain disseminated cancers, because they retain some of the features of their untransformed counterparts. 6,27 For instance, the observation that monocytes play a role in transport of the measles virus during natural infection has led to the successful use of corresponding cell lines as carriers for this virus. 27 Established cell lines derived from promonocytic leukaemias are another example.…”

“…6,27 For instance, the observation that monocytes play a role in transport of the measles virus during natural infection has led to the successful use of corresponding cell lines as carriers for this virus. 27 Established cell lines derived from promonocytic leukaemias are another example. These cells appear as good candidates for the delivery of parvovirus H-1PV because they are permissive for this agent 28 and, Tumour cell carriers of oncolytic viruses Z Raykov and J Rommelaere having retained the capacity of normal monocytes for transendothelial migration, they can transport viruses through the endothelial barrier.…”

“…Most in vitro assays rely on measuring cytotoxicity or on estimating syncytia formation upon co-cultivation of infected carriers with susceptible target cells in the presence and absence of virus-specific antibodies. 5,27 Successful protection is exemplified by the results of a recent experiment carried out in our laboratory, where we tested the effect of an H-1PV-specific rat antiserum (diluted 1:200) on the ability of H-1PV to infect sensitive transformed cells. The parvovirus was delivered at the same total dose in two different ways, as naked virions and by producer carrier cells (effector-to-target cell ratio, 1:10).…”