Herpes virus strains

Abstract

The present invention provides a herpes virus with improved oncolytic properties which comprises a gene encoding an immunomodulatory cytokine and which lacks a functional ICP34.5 gene and a functional ICP47 encoding gene.

1 . A herpes virus which comprises a gene encoding an immunomodulatory protein, which lacks a functional ICP34.5 encoding gene and a functional ICP47 encoding gene and which is replication competent in tumour cells. 
     
     
         2 . A virus according to  claim 1  wherein said immunomodulatory gene is a cytokine, a chemokine or a protein capable of regulating T cell proliferation. 
     
     
         3 . A virus according to  claim 2  wherein said cytokine is GM-CSF, said chemokine is RANTES or said protein is B7.1, B7.2 or CD40L. 
     
     
         4 . A virus according to  claim 1  which encodes two or more immunomodulatory proteins. 
     
     
         5 . A virus according to  claim 1  which further lacks a functional gene encoding ICP6, glycoprotein H or thymidine kinase. 
     
     
         6 . A virus according to  claim 1  which further lacks a gene encoding functional copy of a protein capable of inhibiting dendritic cell function. 
     
     
         7 . A virus according to  claim 6  in which said protein capable of inhibiting dendritic cell function is UL43 or vhs. 
     
     
         8 . A virus according to  claim 1  which is a strain of herpes simplex virus 1 or 2. 
     
     
         9 . A virus according to  claim 1  which is a non-laboratory virus strain. 
     
     
         10 . A virus according to  claim 9  wherein said non-laboratory strain: (a) has undergone one year or less in culture since isolation of its unmodified precursor strain from its host, or (b) has undergone 100 or less cycles of serial passage since isolation of unmodified precursor strain from its host, or (c) has a greater ability than a reference laboratory strain with equivalent modifications to infect or replicate in a tumour cell, to kill tumour cells, or to spread between cells in tissue, or (d) has substantially the ability of its unmodified precursor strain in respect of one or more of the properties defined in (c). 
     
     
         11 . A virus according to  claim 10  wherein, in (c), said greater ability in a statistically significant greater ability; or wherein, in (d), substantially the same ability is the same ability or at an ability not statistically different. 
     
     
         12 . A virus according to  claim 10  wherein the non-laboratory strain is an HSV strain and the reference strain is HSV1 strain 17 + , HSV1 strain F as HSV1 strain KOS with equivalent modifications to the non-laboratory strain. 
     
     
         13 . A virus according to  claim 1  which is derived from HSV1 JSI as deposited at the European collection of cell cultures (ECAAC) under provisional accession number 01010209. 
     
     
         14 . A virus according to  claim 1  for use in a method of treatment of the human or animal body by therapy. 
     
     
         15 . Use of a virus according to  claim 1  in the manufacture of a medicament for the treatment of cancer. 
     
     
         16 . Use according to  claim 15  wherein said medicament is for direct intra-tumoral inoculation. 
     
     
         17 . A pharmaceutical composition comprising as active ingredient a virus according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         18 . A method of treating a tumour in an individual in need thereof by administering to said individual an effective amount of a virus according to  claim 1 . 
     
     
         19 . An agent for treating cancer comprising a herpes virus which comprises a gene encoding an immunomodulatory cytokine, which lacks a functional ICP34.5-encoding gene and a functional ICP47 encoding gene and which is replication competent in tumour cells. 
     
     
         20 . HSV1 strain JSI as deposited as the European Collection of Cell. Cultures (ECACC) under provisional accession number 01010209, or an HSV1 strain derived therefrom. 
     
     
         21 . A method of treating cancer in an individual in need thereof by administering to a tumor in said individual a therapeutically effective amount of a herpes simplex virus which: (i) comprises an immunostimulatory protein; (ii) lacks a functional ICP34.5 encoding gene and a functional ICP47 encoding gene; and (iii) is replication competent in infected tumor cells. 
     
     
         22 . The method of  claim 21  wherein said virus kills infected tumor cells by oncolysis and stimulates an anti-tumor immune response. 
     
     
         23 . The method of  claim 21  wherein tumor cells infected with said virus and non-infected tumor cells are killed. 
     
     
         24 . The method of  claim 23  wherein said virus is administered to a primary tumor and tumor cells in the primary tumor and tumor cells elsewhere that have spread from the primary tumor site are killed. 
     
     
         25 . The method of  claim 23  wherein said cancer is selected from the group consisting of prostate, breast, liver, endometrial, bladder, colon or cervical carcinoma, melanoma, lymphoma, glioma and sarcoma. 
     
     
         26 . The method of  claim 23  wherein said cancer is selected from the group consisting of prostate, breast, lung, liver, endometrial, bladder, colon or cervical carcinoma, adenocarcinoma, melanoma, lymphoma, glioma and sarcoma. 
     
     
         27 . The method of  claim 21  wherein said virus is administered by direct intratumoral inoculation. 
     
     
         28 . The method of  claim 21  wherein said virus is administered to a blood vessel supplying the tumor. 
     
     
         29 . The method of  claim 21  wherein said immunostimulatory protein is GM-CSF. 
     
     
         30 . The method of  claim 21  wherein said immunostimulatory protein is a cytokine, chemokine or protein capable of regulating T cell proliferation. 
     
     
         31 . The method of  claim 21  wherein said virus further lacks a functional gene encoding ICP6, glycoprotein H or thymidine kinase. 
     
     
         32 . The method of  claim 21  wherein said virus is a strain of herpes simplex virus 1 or 2. 
     
     
         33 . The method of  claim 21  wherein said virus is a clinical isolate. 
     
     
         34 . The method of  claim 33  wherein said clinical isolate is derived from HSV1 JS1 as deposited at the European collection of cell cultures (ECAAC) under accession number 01010209. 
     
     
         35 . A herpes simplex virus which: (i) comprises a gene encoding an immunostimulatory protein selected from GM-CSF and a chemokine; (ii) lacks a functional ICP34.5 encoding gene and a functional ICP47 encoding gene; and (iii) is replication competent in infected tumor cells. 
     
     
         36 . The virus of  claim 35  wherein said immunostimulatory protein is GM-CSF. 
     
     
         37 . The virus of  claim 35  which comprises a functional UL43 gene and/or a functional gene encoding vhs. 
     
     
         38 . The virus of  claim 35  which further lacks a functional gene encoding ICP6, glycoprotein H or thymidine kinase. 
     
     
         39 . The virus of  claim 35  which is a strain of herpes simplex virus 1 or 2. 
     
     
         40 . The virus of  claim 35  which is a clinical isolate. 
     
     
         41 . A pharmaceutical composition comprising as active ingredient a virus according to  claim 35  and a pharmaceutically acceptable carrier or diluent. 
     
     
         42 . A pharmaceutical composition comprising as active ingredient a virus according to  claim 36  and a pharmaceutically acceptable carrier or diluent. 
     
     
         43 . A pharmaceutical composition according to  claim 42 , wherein the virus is derived from HSV1 JS1 as deposited at the European collection of cell cultures (ECAAC) under accession number 01010209.