Avirulent oncolytic herpes simplex virus strains engineered to counter the innate host response
The present invention relates to an avirulent, oncolytic herpes simplex virus modified from a wild-type herpes simplex virus so that both γ 1 34.5 genes of the virus have been deleted and each replaced with an interferon-resistance gene that is expressed as an immediate-early gene. The present invention also relates to a pharmaceutical composition that includes the modified herpes simplex virus of the present invention and a pharmaceutically acceptable vehicle for in situ administration to tumor cells. Also provided in the present invention are methods for killing tumor cells in a subject and for immunizing a subject against an infectious disease, cancer, or an autoimmune disease that involve administering to a subject the modified avirulent, oncolytic herpes simplex virus of the present invention.
1. An avirulent, oncolytic herpes simplex virus having an intact U s 12 gene and an endogenous U s 11 gene expressed as a late gene, wherein said virus is modified from the wild-type herpes simplex virus with both γ 1 34.5 genes of the virus being deleted and U s 11 genes that are expressed as immediate-early (IE) genes being inserted into the γ 1 34.5 gene locus in place of both γ 1 34.5 genes.
2. The oncolytic modified virus according to claim 1 , wherein the interferon-resistance gene is under the control of a herpes simplex virus (IE) promoter.
3. The oncolytic modified virus according to claim 2 , wherein the promoter is an α27 IE promoter.
4. The oncolytic modified herpes simplex virus according to claim 1 further comprising an ICP 6-inactivating mutation.
5. The oncolytic modified virus according to claim 1 , wherein the wild-type herpes simplex virus is herpes simplex virus type 1 (HSV-1).
6. The oncolytic modified virus according to claim 5 , wherein the HSV-1 is a strain selected from the group consisting of HSV-1 strain 17, strain KOS, strain F, strain Patton, and any clinical isolate.
7. A pharmaceutical composition comprising:
the avirulent, oncolytic modified herpes simplex virus according to claim 1 , and a pharmaceutically acceptable vehicle for in situ administration to tumor cells.
8. The pharmaceutical composition according to claim 7 , wherein the wild-type herpes simplex virus is herpes simplex virus type 1.
9. A method for killing tumor cells in a subject comprising:
administering to a subject the avirulent, oncolytic modified herpes simplex virus according to claim 1 under conditions effective to kill tumor cells in the subject.
10. The method according to claim 9 , wherein the tumor cells are selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, medulloblastoma, melanoma cells, pancreatic cancer cells, prostate carcinoma cells, breast cancer cells, lung cancer cells, colon cancer cells, lymphoma cells, hepatoma cells, mesothelioma and epidermoid carcinoma cells.
11. The method according to claim 9 , wherein the administering is carried out by injection, infusion, instillation or inhalation.
12. The method according to claim 9 , wherein the subject is a mammal.
13. The method according to claim 12 , wherein the mammal is a human.