Viruses for the treatment of cellular proliferative disorders

• US 7,252,817 B2
• Filed: 04/18/2003
• Issued: 08/07/2007
• Est. Priority Date: 11/12/1999
• Status: Expired due to Term

• Current Assignee: Oncolytics Biotech Incorporated
• Original Assignee: Oncolytics Biotech Incorporated
• Inventors: Coffey, Matthew C., Thompson, Bradley G.
• Primary Examiner(s): Campell; Bruce R.
• Assistant Examiner(s): LI, BAO Q
• Application Number:
  US10/418,290
• Publication Number:
  US 20040057929A1
• Time in Patent Office: 1,572 Days
• Field of Search: 424/93.1, 424/205.1, 435/91.33, 435/91.4, 435/5, 435/7.23, 435/236, 435/239, 435/230.1, 435/205.1, 534/339
• US Class Current: 424/93.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/13 Tumour cells, irrespective of tissue of origin tumour vaccines A61K39/00
• CPC Class Codes: A61K 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 35/761 Adenovirus
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2710/10032 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/24132 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Abstract

Methods for treating cell proliferative disorders by administering virus to proliferating cells having an activated Ras-pathway are disclosed. The virus is administered so that it ultimately directly contacts proliferating cells having an activated Ras-pathway. Proliferative disorders include but are not limited to neoplasms. The virus is selected from modified adenovirus, modified HSV, modified vaccinia virus and modified parapoxvirus orf virus. Also disclosed are methods for treating cell proliferative disorders by further administering a immunosuppressive agent.

Claims

1. A method for treating a neoplasm in a mammal, comprising the steps of:

(a) selecting a mammal with a neoplasm wherein cells of the neoplasm are unable to activate a PKR-mediated response to viral infection; and

(b) administering to the cells of the neoplasm an effective amount of at least one modified HSV under conditions that result in substantial lysis of the cells of the neoplasm, wherein in the modified HSV, the <sub>γ

1</sub>34.5 gene is lacking, inhibited or mutated such that PKR activation is not blocked.

2. The method of claim 1, wherein the cells of the neoplasm comprise PKR that is unable to be phosphorylated.

3. The method of claim 1, wherein the modified HSV does not transcribe the _γ

134.5 gene.

4. The method of claim 1, wherein the modified HSV comprises a mutated _γ

134.5 gene.

5. The method of claim 1, wherein the neoplasm is metastatic.

6. The method of claim 1, wherein:

substantially all the neoplasm is surgically removed prior to the administration of the modified HSV; and

the modified HSV is administered the surgical site in an amount sufficient to result in substantial oncolysis of any remaining neoplasm.

7. The method of claim 1 further comprising a step selected from the group consisting of:

i) administering to the cells of the neoplasm in said mammal an effective amount of an immune suppressive agent;

ii) removing anti-virus antibodies from said mammal;

iii) administering anti-antivirus antibodies to said mammal; and

iv) suppressing the immune system of the mammal.

8. The method of claim 1 wherein the mammal is selected from the group consisting of dogs, cats, sheep, goats, cattle, horses, pigs, humans and non-human primates.

9. The method of claim 1 wherein the mammal is human.

10. The method of claim 1 wherein the neoplasmn is selected from the group consisting of lung cancer, prostate cancer, colorectal cancer, thyroid cancer, renal cancer, adrenal cancer, liver cancer, pancreatic cancer, breast cancer and central and peripheral nervous system cancer.

11. The method of claim 1 wherein the neoplasm is a hematopoictic neoplasm.

12. The method of claim 1 wherein the modified HSV is administered by injection directly to the neoplasm or by a route selected from the group consisting of intravenous, intravascular, intramuscular, subcutaneous, and intraperitoneal administration.

13. The method of claim 1, further comprising the administration of an effective amount of at least one chemotherapeutic agent.

14. The method of claim 1 wherein the modified HSV is administered in a single dose.

15. The method of claim 1 wherein the modified HSV is administered in more than one dose.

16. The method of claim 1 wherein the mammal is immunocompetent.

17. The method of claim 1 wherein the modified HSV is immunoprotected by digesting the outer capsid of the modified HSV with a protease.

18. The method of claim 1 wherein the modified HSV is encapsulated in a micelle or liposome.

19. The method of claim 1, further comprising surgically removing substantiaJly all the neoplasm prior to the administration of the modified HSV.