Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice

Abstract

IntroductionStandard gene-therapy approaches to cancer treatment, such as transfer of suicide genes that confer sensitivity to prodrugs, have limitations as cytoreductive strategies owing to insufficient bystander effects of the therapeutic gene combined with suboptimal transduction efficiency of currently available gene delivery vectors. A more compelling approach in this situation is the use of a vector or virus that is able to replicate within the tumor tissue, resulting in direct cell death through cytolysis or toxicity of viral proteins. Ideally, such an agent should also be capable of stimulating a potent immune response to the tumor within which it can replicate.Studies throughout the twentieth century have documented the lytic effects of various viruses on many types of human cancer, 1 and systematic study of candidate oncolytic viruses is intensifying. Viruses under investigation as oncolytic agents include human adenoviruses, ONYX-015, 2,3 reovirus, 4 herpes viruses 5,6 and vesicular stomatitis virus. 7 All of these viruses have shown promise in preclinical studies, and clinical studies of some of the agents are now in progress. 8 Viruses of the Paramyxoviridae family are also oncolytic. Almost 30 years ago, the human paramyxovirus, mumps, was administered to 90 patients with advanced malignancy, 9 resulting in significant (although mostly short-lived) responses. Toxicity was minimal. More recently, Newcastle disease virus, an avian paramyxovirus, has also shown promising results in preclinical studies, [10][11][12] and clinical trials in human subjects have begun.In this study, we have investigated another human paramyxovirus, measles, as a potential antitumor agent for lymphoid malignancies. Measles virus (MV) may be particularly promising as an oncolytic virus for the treatment of lymphoid malignancy for a number of reasons. First, a nonpathogenic strain of MV is available, well characterized, and safe. Live attenuated MV vaccines, derived from the Edmonston-B strain (MV-Ed), 13 have been used worldwide for more than 30 years, and in excess of 160 million doses have been administered in the United States alone with an excellent safety record. Second, although many human cell types are permissive for MV infection in vitro, in the presence of an intact immune system, virus replication after natural infection is limited to a few cell types in vivo. Lymphoid organs are prominent sites of MV replication; indeed, multinucleated giant cells develop during infection in lymph nodes as a result of gross cell-cell fusion. 14 Third, we have recently shown that expression of virally derived fusogenic membrane glycoproteins in tumor cells, including MV fusion (F) and hemagglutinin (H) glycoproteins, 15-17 results in a potent cytopathic effect mediated by massive cell-cell fusion. The considerable local bystander effect implies that transduction of all tumor cells would not be necessary to achieve significant tumor cell kill. However, the use of MV as a replicating vector with which to deliver the F and H glycopro...

Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas

“…6 Once MV-Edm has infected tumor cells it spreads to noninfected tumor bystander cells by cell-to-cell contact. 7,8 MV-Edminfected tumor cells form syncytia 9 induced by the F-protein of the virus, eventually leading to cell death that includes programmed cell death. 10 MV-Edm has been shown in animal models to have oncolytic activity against human lymphoma, 9 multiple myeloma, 11 ovarian cancer, 12,13 malignant glioma, 5 fibrosarcoma 14 and against cutaneous T-cell lymphoma in patients.…”

High CD46 Receptor Density Determines Preferential Killing of Tumor Cells by Oncolytic Measles Virus

“…Live attenuated Edmonston B strain of measles virus (MV-Edm) has potent and specific oncolytic activity against a variety of human tumors, including lymphoma, multiple myeloma, epithelial ovarian cancer, and glioma (1)(2)(3)(4)(5)(6). MVCEA, a recombinant MV-Edm genetically modified to express human carcinoembryonic antigen (CEA) as a biologically inert soluble marker for noninvasive monitoring of the profiles of viral gene expression, is being tested in a Phase I clinical trial for patients with recurrent epithelial ovarian cancer (7).…”

Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

“…Measles virus (MV), a negative sense, ssRNA virus has well documented lytic activity in several in vivo models of human cancer (2)(3)(4)(5) and is already in early-phase clinical trials (6). Mechanisms of oncolytic activity, particularly in vivo, are unclear.…”