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

Abstract

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.

1 . A method of treating cancer comprising administering to a subject with cancer a pharmaceutical composition comprising an effective amount of a chimeric Vesicular stomatitis Indiana virus (VSV) virus to treat the cancer,
 wherein the chimeric VSV virus comprises a VSV background with one or more heterologous viral glycoproteins in place of the VSV G-protein,   wherein the G protein is not from Lymphocytic choriomeningitis (LCMV).   
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1  wherein the VSV background is VSV Indiana, VSV New Jersey, VSV Alagoas, (formerly Indiana 3), VSV Cocal (formerly Indiana 2), VSV Chandipura, VSV Isfahan, VSV San Juan, VSV Orsay, VSV Glasgow, or a recombinant VSV comprising at least 1 gene from two or more VSV strains or serotypes selected from the group consisting of VSV Indiana, VSV New Jersey, VSV Alagoas, (formerly Indiana 3), VSV Cocal (formerly Indiana 2), VSV Chandipura, VSV Isfahan, VSV San Juan, VSV Orsay, and VSV Glasgow. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1  wherein the chimeric VSV virus further comprises one or more additional heterologous proteins. 
     
     
         8 . The method of  claim 7  wherein the chimeric VSV virus's genome encodes the one or more heterologous genes. 
     
     
         9 . The method of  claim 7  wherein the one or more additional heterologous proteins is a therapeutic protein, a reporter, a vaccine antigen, a targeting moiety, or a combination thereof. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1  wherein the cancer is selected from the group consisting of multiple myeloma, bone, bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, and uterine. 
     
     
         13 . The method of  claim 12  wherein the brain cancer is oligodendroglioma, meningioma, supratentorial ependymona, pineal region tumors, medulloblastoma, cerebellar astrocytoma, infratentorial ependymona, brainstem glioma, schwannomas, pituitary tumors, craniopharyngioma, optic glioma, and astrocytoma. 
     
     
         14 . The method of  claim 12  wherein the brain cancer is glioblastoma. 
     
     
         15 . The method of  claim 1  wherein the virus is in a dosage of between 10 2  and 10 12  PFU. 
     
     
         16 . The method of  claim 1  wherein the pharmaceutical composition is administered locally to the site of the cancer. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1  wherein the pharmaceutical composition is administered systemically to the subject. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1  further comprising administering the subject a second therapeutic agent. 
     
     
         22 . The method of  claim 21  wherein the second therapeutic agent is an anticancer agent, a therapeutic protein, or an immunosuppressant. 
     
     
         23 .- 30 . (canceled) 
     
     
         31 . The method of  claim 1  wherein the chimeric VSV show little or no ability to infect normal or health neurons. 
     
     
         32 . A method of treating a subject for cancer comprising
 (a) infecting isolated cancer cells with an effective amount of a chimeric VSV virus   (b) administrating the infected cells to the subject in an effective amount to induce an immune response against the cancer cells in the subject;   wherein the chimeric VSV virus comprises a VSV background with one or more heterologous viral glycoproteins in place of the VSV G-protein,   wherein the G protein is not from Lymphocytic choriomeningitis (LCMV).   
     
     
         33 . The method of  claim 32  further comprising irradiating the cells to prevent their proliferation. 
     
     
         34 . The method of  claim 32  wherein the subject has cancer. 
     
     
         35 .- 43 . (canceled) 
     
     
         44 . A pharmaceutical dosage unit comprising an effective amount of a chimeric VSV virus to treat cancer in subject in need thereof, wherein the chimeric VSV virus comprises a VSV background with one or more heterologous viral glycoproteins in place of the VSV G-protein,
 wherein the G protein is not from Lymphocytic choriomeningitis (LCMV).   
     
     
         45 .- 50 . (canceled) 
     
     
         51 . The method of  claim 1 , wherein the heterologous glycoprotein is derived from an arenavirus. 
     
     
         52 . The method of  claim 51 , wherein the arenavirus is Ippy virus.