Use of herpes vectors for tumor therapy

Abstract

Eliciting a systemic antitumor immune response, in a patient who presents with or who is at risk of developing multiple metastatic tumors of a given cell type, entails, in one embodiment, inoculating a tumor in the patient with a pharmaceutical composition consisting essentially of (A) a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells and (B) a pharmaceutically acceptable vehicle for the virus, such that an immune response is induced that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor. In another embodiment, the pharmaceutical composition also comprises a defective HSV vector which contains an expressible nucleotide sequence encoding at least one immune modulator. In another embodiment, the pharmaceutical composition contains a second HSV that infects tumor cells but that does not spread in normal cells. According to the latter approach, both the first HSV and the second HSV may have genomes that comprise, respectively, an expressible nucleotide sequence coding for at least one immune modulator. In another embodiment, the pharmaceutical composition comprises, in addition to a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, a viral vector comprising at least one expressible nucleotide sequence coding for at least one immune modulator.

1 - 34 . (canceled)  
   
   
       35 . A herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, with a genome comprising (i) at least one expressible nucleotide sequence encoding at least one immune modulator and (ii) a mutation in the γ34.5 gene.  
   
   
       36 . The HSV of  claim 35 , wherein both copies of said γ34.5 gene are mutated.  
   
   
       37 . The HSV of  claim 35 , wherein said HSV further comprising at least one further gene mutation.  
   
   
       38 . The HSV of  claim 35 , wherein said at least one further gene mutation is in ribonucleotide reductase.  
   
   
       39 . The HSV of  claim 35 , wherein said HSV is G207.  
   
   
       40 . The HSV of  claim 35 , wherein said immune modulator is selected from the group consisting of a cytokine, a co-stimulatory molecule and a chemokine.  
   
   
       41 . The HSV of  claim 35 , wherein said immune modulator is selected from the group consisting of IL-1, L-2, IL-3, IL-4, IL-6, IL-7, IL-12, G-CSF, GM-CSF, IFN-α, IFN-γ, TNF-α and B7  
   
   
       42 . The HSV of  claim 35 , wherein said immune modulator is selected from the group consisting of GM-CSF and IL-12.  
   
   
       43 . The HSV of  claim 35 , wherein the tumor cells are of a type selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.  
   
   
       44 . A composition comprising the HSV of  claim 35  and a pharmaceutically acceptable vehicle for said HSV.