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.

What is claimed is:  
     
         1 . A method of 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, comprising the step of 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.    
     
     
         2 . The method of  claim 1 , wherein the virus replicates in dividing cells and exhibits attenuated replication in non-dividing cells.  
     
     
         3 . The method of  claim 2 , wherein the virus is incapable of expressing both (i) a functional γ34.5 gene product and (ii) a ribonucleotide reductase.  
     
     
         4 . The method of  claim 3 , wherein the virus is the multi-gene mutant G207.  
     
     
         5 . The method of  claim 1 , wherein the virus is replication-defective.  
     
     
         6 . The method of  claim 5 , wherein the virus is a temperature-sensitive mutant.  
     
     
         7 . The method of  claim 6 , wherein the virus is the ICP4 mutant tsK.  
     
     
         8 . The method of  claim 1 , wherein the virus is conditionally replication-competent.  
     
     
         9 . The method of  claim 8 , wherein the virus is the mutant G92A.  
     
     
         10 . The method of  claim 1 , wherein the virus is of a vaccine strain.  
     
     
         11 . The method of  claim 1 , wherein the virus is an HSV type-1 (HSV-1) virus.  
     
     
         12 . The method of  claim 1 , wherein the virus is an HSV type-2 (HSV-2) virus.  
     
     
         13 . The method of  claim 1 , wherein the tumor cells are of a type selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.  
     
     
         14 . The method of  claim 1 , wherein the tumor cells are selected from the group consisting of melanoma cells, pancreatic cancer cells, prostate carcinoma cells, head and neck cancer cells, breast cancer cells, lung cancer cells, colon cancer cells, lymphoma cells, ovarian cancer cells, renal cancer cells, neuroblastomas, squamous cell carcinomas, medulloblastomas, hepatoma cells and mesothelioma and epidermoid carcinoma cells.  
     
     
         15 . The method of  claim 1 , wherein the genome of the herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator.  
     
     
         16 . The method of  claim 15 , wherein the immune modulator is selected from the group consisting of cytokines, chemokines, and co-stimulatory molecules.  
     
     
         17 . The method of  claim 1 , wherein the patient presents with multiple metastatic tumors.  
     
     
         18 . A method of 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, comprising the step of inoculating a tumor in the patient with a pharmaceutical composition comprising: 
 (A) a herpes simplex virus that infects tumor cells but that does not spread in normal cells, and whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor,    (B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator, and    (C) a pharmaceutically acceptable vehicle for the virus and defective vector,    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.    
     
     
         19 . The method of  claim 18 , wherein the immune modulator is selected from the group consisting of cytokines, chemokines, and co-stimulatory molecules.  
     
     
         20 . A herpes simplex virus that is incapable of expressing both (i) a functional γ34.5 gene product and (ii) a ribonucleotide reductase, wherein the genome of the virus comprises at least one expressible nucleotide sequence encoding at least one immune modulator.  
     
     
         21 . The virus of  claim 20 , wherein the virus is the multi-gene mutant G207, the genome of which has been altered to incorporate the expressible nucleotide sequence.  
     
     
         22 . A herpes simplex virus ICP4 mutant tsK, the genome of which has been altered to incorporate at least one expressible nucleotide sequence coding for at least one immune modulator.  
     
     
         23 . A composition for 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, comprising: 
 (A) a herpes simplex virus that is incapable of expressing both (i) a functional γ34.5 gene product and (ii) a ribonucleotide reductase, and    (B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.    
     
     
         24 . The composition of  claim 23 , wherein the virus is the multi-gene mutant G207.  
     
     
         25 . A composition for 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, comprising: 
 (A) a herpes simplex virus that is replication-defective, and whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor, and    (B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.    
     
     
         26 . The composition of  claim 25 , wherein the virus is the ICP4 mutant tsK.  
     
     
         27 . A composition for 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, comprising: 
 (A) a herpes simplex virus that is conditionally replication-competent, and    (B) a defective herpes simplex virus vector containing at least one expressible nucleotide sequence encoding at least one immune modulator.    
     
     
         28 . The composition of  claim 27 , wherein the virus is the mutant G92A.  
     
     
         29 . A method of 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, comprising the step of inoculating a tumor in the patient with a pharmaceutical composition comprising: 
 (A) a first herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, whose immunological properties consist essentially of inducing an immune response that is specific for the tumor cell type and that kills cells of the inoculated tumor and of a non-inoculated tumor,    (B) a second herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, and    (C) a pharmaceutically acceptable vehicle for the viruses,    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.    
     
     
         30 . The method of  claim 29 , wherein the genome of the second herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator.  
     
     
         31 . A method of 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, comprising the step of inoculating a tumor in the patient with a pharmaceutical composition comprising: 
 (A) a first herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, wherein the genome of the first herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator,    (B) a second herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells, wherein the genome of the second herpes simplex virus comprises at least one expressible nucleotide sequence coding for at least one immune modulator, and    (C) a pharmaceutically acceptable vehicle for the viruses,    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.    
     
     
         32 . A method of 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, comprising the step of inoculating a tumor in the patient with a pharmaceutical composition comprising: 
 (A) a herpes simplex virus (HSV) that infects tumor cells but that does not spread in normal cells,    (B) a viral vector comprising at least one expressible nucleotide sequences coding for at least one immune modulator, and    (C) a pharmaceutically acceptable vehicle for the virus and viral vector,    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.    
     
     
         33 . The method of  claim 32 , wherein the viral vector is selected from the group consisting of adenoviral vectors, adenovirus-associated vectors, retroviral vectors, and vaccinia virus vectors.  
     
     
         34 . The method of  claim 32 , wherein the immune modulator is selected from the group consisting of cytokines, chemokines, and co-stimulatory molecules.