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. A vaccine comprising:
(a) a modified herpes simplex virus (HSV), and
(b) a pharmaceutically acceptable vehicle for in situ administration to the subject,
wherein the modified HSV has an intact U s 12 gene and an endogenous U s 11 gene expressed as a late gene, and is modified from a wild-type HSV with both γ 1 34.5 genes of the virus being deleted and U s 11 genes that are expressed as intermediate early (IE) genes being inserted in the γ 1 34.5 gene locus in place of both γ 1 34.5 genes.
2. The vaccine of claim 1 , wherein the modified HSV is avirulent.
3. The vaccine of claim 1 , wherein the U s 11 genes are under control of an HSV IE promoter.
4. The vaccine of claim 1 , wherein the promoter is an α27 IE promoter.
5. The vaccine of claim 1 , wherein the modified HSV further comprises an ICP 6-inactivating mutation.
6. The vaccine of claim 1 , wherein the wild-type HSV is a herpes simplex virus type 1 (HSV-1).
7. The vaccine of claim 6 , 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 thereof.
8. The vaccine of claim 1 , wherein the wild-type HSV is a herpes simplex virus type 2 (HSV-2).
9. The vaccine of claim 8 , wherein the HSV-2 is a strain selected from the group consisting of HSV-2 strain G, strain HG52 and any clinical isolate thereof.
10. The vaccine of claim 1 , which is administered by injection, infusion, instillation or inhalation.
11. The vaccine of claim 1 , which is suitable for immunizing a mammal.
12. The vaccine of claim 11 , wherein the mammal is a human.