Use of mutant Herpes Simplex Virus-2 for cancer therapy
The present invention is directed to the composition and use of a modified Herpes Simplex Virus Type 2 (HSV-2) as a medicament in the treatment of cancer. The modified HSV-2 has fusogenic activity, and comprises a modified/mutated ICP 10 polynucleotide encoding a polypeptide having ribonucleotide reductase activity and lacking protein kinase activity.
1. A method of selectively killing cancer cells in a subject in need thereof, the method comprising:
intratumorally or systemically administering to the subject in need thereof an effective amount of a fusogenic mutant Herpes Simplex Virus Type 2 (HSV-2), wherein the fusogenic mutant HSV-2 comprises a modified ICP10 coding region lacking nucleotides 1 to 1204 of an endogenous ICP10 coding region, wherein said fusogenic mutant HSV-2 comprises the modified ICP10 operably linked to an endogenous or a constitutive promoter and expresses a modified ICP10 polypeptide that lacks protein kinase (PK) activity but retains ribonucleotide reductase activity, and
wherein said administration provides for selective killing of cancer cells by direct cytolysis and syncytia formation in cells that are susceptible to replication of the fusogenic mutant HSV-2.
2. The method of claim 1 , wherein the modified ICP 10 coding region further expresses a reporter protein selected from the group consisting of green fluorescent protein, β-galactosidase, luciferase and Herpes Simplex Virus thymidine kinase (HSV tk).
3. The method of claim 1 , wherein the modified ICP 10 coding region comprises an immunomodulatory gene selected from the group consisting of tumor necrosis factor, interferon alpha, interferon beta, interferon gamma, interleukin-2, interleukin 12, GM-CSF, F42K, MIP-1, MIP-1β and MCP-1.
4. The method of claim 1 , wherein the modified ICP 10 coding region further expresses a fusogenic membrane glycoprotein.
5. The method of claim 4 , wherein the fusogenic membrane glycoprotein is selected from the group consisting of a gibbon ape leukemia virus envelope fusogenic membrane glycoprotein, a murine leukemia virus envelope protein, a retroviral envelope protein lacking the cytoplasmic domain, a measles virus fusion protein, an HIV gp160 protein, an SIV gp160, a retroviral envelope protein, an Ebola virus glycoprotein and an influenza virus haemagglutinin.
6. The method of claim 1 , wherein the cancer cells are selected from the group consisting of breast cancer cells, ovarian cancer cells, lung cancer cells, skin cancer cells, prostate cancer cells, pancreatic cancer cells, colon cancer cells, brain cancer cells, liver cancer cells, thyroid cancer cells, kidney cancer cells, spleen cancer cells, leukemia cells, stomach cancer cells and bone cancer cells.