Yale University

Leland Stanford Junior University

Anthony N Van Den Pol

Guido Wollmann

H Craig Heller

Chimeric viruses having a vesicular stomatitis virus (VSV) background where the VSV G protein is supplemented or replaced with an alphavirus glycoprotein(s), or a functional fragment(s) thereof, are provided. A preferred alphavirus is Chikungunya virus. In particular embodiments, the glycoprotein(s) is or includes E3, E2, K6, and E1 proteins of an alphavirus, preferably Chikungunya virus. Methods of using the chimeric viruses for treatment of cancers, particularly brain cancers and metastasis thereof are also provided. In some embodiments, the chimeric viruses retain superior oncolytic activity to infect and destroy cancer cells selectively, such as glioblastoma and intracranial melanoma metastases. In some embodiments, the chimeric viruses have reduced toxicity to e.g., heathy cells relative to a control such as the parent VSV with the VSV G protein.

Methods for treatment of cancer using chikungunya-VSV chimeric virus

Methods of treating cancer including administering to a subject with cancer a pharmaceutical composition including an effective amount of a chimeric VSV virus are disclosed. The chimeric viruses are based on a VSV background where the VSV G protein is replaced with one or more heterologous viral glycoproteins. In the most preferred embodiment, the VSV G protein is replaced with the glycoprotein from Lassa virus or a functional fragment thereof. The resulting chimeric virus is an oncolytic virus that is attenuated and safe in the brain, yet still retains sufficient oncolytic activity to infect and destroy cancer cells such glioblastoma, and to generate an immune response against infected cancer cells. Methods of using chimeric viruses as a platform for immunization against other pathogenic microbes are also provided.

Chimeric VSV virus compositions and methods of use thereof for treatment of cancer

Oncolytic VSV viruses have been developed as a strategy for combating cancer. The present invention includes mutant VSV that have one or more mutations in the nucleic acid sequence encoding the viral genome that increase the oncolytic potential of the virus. Pharmaceutical compositions including oncolytic virus disclosed herein are also provided. Pharmaceutical compositions containing virus and one or more excipients may be for systemic or local administration. Methods of administering an effective amount of the compositions for treating cancer are disclosed. Preferred routes of administration include intratumeral and intravenous injection, and intranasal delivery. Administration of the disclosed compositions containing oncolytic viruses may be coupled with surgical, radiologic, other therapeutic approaches to treatment of cancer. Methods of manufacturing mutant VSV viruses exhibiting desired properties include applying selective pressure, and through directed or random mutagenesis.

Compositions and methods of use of an oncolytic vesicular stomatitis virus

A method for phase shifting the circadian pacemaker or treating seasonal affective disorder in a subject is disclosed. The method includes exposing the subject's eye region to a given-intensity light flash having a flash duration of between about 1-500 msec, at a periodicity of at least about one flash per minute, over a selected time period effective, were the subject exposed to a continuous light pulse of the same intensity for this period, to phase shift the circadian pacemaker or treat the seasonal affective disorder in the subject. Also disclosed is a device for practicing the method.

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Branford, CT, United States of America

Anthony N Van Den Pol