Oncolytic vaccinia virus cancer therapy
Embodiments of the invention are directed methods that include a thymidine kinase deficient vaccinia virus. The methods include administering the vaccinia virus at increased viral concentrations. Further aspects of the invention include methods for inducing oncolysis or collapse of tumor vasculature in a subject having a tumor comprising administering to a subject at least 1×10 8 infectious viral particles of a TK-deficient, GM-CSF-expressing, replication-competent vaccinia virus vector sufficient to induce oncolysis of cells in the tumor.
1. A method of inducing oncolysis in a human subject having a tumor comprising administering to said subject one or more single doses of a phannaceutical composition comprising a pharmaceutically acceptable carrier and a purified TK-deficient, human GM-CSF-expressing, replication-competent Wyeth strain vaccinia virus vector wherein said single dose comprises between 1×10 9 pfu and 1×10 10 pfu, and wherein said administering comprises injection into the tumor mass or tumor vasculature, whereby oncolysis is induced in said tumor and in at least one tumor that is not injected with the virus.
2. The method of claim 1 , wherein the subject is administered 2 or more doses.
3. The method of claim 2 , wherein 2 or more doses are administered over a period of at least 7 days.
4. The method of claim 1 , wherein said tumor is a brain cancer tumor, a head & neck cancer tumor, an esophageal cancer tumor, a skin cancer tumor, a lung cancer tumor, a thymic cancer tumor, a stomach cancer tumor, a colon cancer tumor, a liver cancer tumor, an ovarian cancer tumor, a uterine cancer tumor, a bladder cancer tumor, a testicular cancer tumor, a rectal cancer tumor, a breast cancer tumor, or a pancreatic cancer tumor.
5. The method of claim 4 , wherein the tumor is a hepatocellular carcinoma or a melanoma.
6. The method of claim 1 , wherein said tumor is recurrent.
7. The method of claim 1 , wherein said tumor is primary.
8. The method of claim 1 , wherein said tumor is metastatic.
9. The method of claim 1 , wherein said tumor is multi-drug resistant.
10. The method of claim 1 , further comprising administering to said subject a second cancer therapy.
11. The method of claim 1 , further comprising a second cancer therapy selected from chemotherapy, biological therapy, radiotherapy, immunotherapy, hormone therapy, anti-vascular therapy, cryotherapy, toxin therapy or surgery.
12. The method of claim 1 , wherein said subject is immunocompromised.
13. The method of claim 1 , wherein said tumor is non-resectable prior to treatment and resectable following treatment.
14. The method of claim 1 , further comprising assessing tumor cell viability following treatment.
15. The method of claim 1 , further comprising imaging said tumor prior to administration.
16. The method of claim 1 , wherein said vaccinia virus comprises one or more modified viral genes.
17. The method of claim 16 , wherein the one or more modified viral genes comprise one or more of:
(a) an interferon-modulating polypeptide;
(b) a complement control polypeptide;
(c) a TNF or chemokine-modulating polypeptide;
(d) a serine protease inhibitor;
(e) a IL-1β modulating polypeptide;
(f) a non-infectious EEV form polypeptide; or
(g) a viral polypeptide that act to inhibit release of infectious virus from cells (anti-infectious virus form polypeptide).
18. The method of claim 2 , wherein 2 or more doses are administered over a period of at least 6 weeks.
19. The method of claim 1 , wherein oncolysis is induced in more than 90% of cells in said tumor.
20. The method of claim 1 , wherein the composition is administered weekly or every other week.