Viral mutant HSV mediated destruction of neoplastic cells

• US 6,770,274 B1
• Filed: 07/11/1994
• Issued: 08/03/2004
• Est. Priority Date: 09/14/1990
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Coen, Donald M., Martuza, Robert L.
• Primary Examiner(s): Crouch, Deborah
• Application Number:
  US08/272,516
• Time in Patent Office: 3,676 Days
• Field of Search: 435/172.1, 435/5, 435/320.1, 435/172.3, 435/240.2, 514/44, 424/230.1, 424/231.1, 424/233.1, 424/93.1, 424/93.2, 424/93.6
• US Class Current: 424/93.2
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: C12N 2710/16632 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention is drawn to compositions and methods for selectively killing neoplastic cells. Altered viruses are utilized which are capable of replication in neoplastic cells while sparing surrounding normal tissue.

Claims

1. A method for selectively killing nervous system tumor cells in a mammal, said method comprising:

a) directly administering to a tumor in said mammal a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the γ

-34.5 gene; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells; and

wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) killing said nervous system tumor cells.

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

3. The method of claim 1 wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

4. The method of claim 3, wherein the tumor is a glioblastoma.

5. The method of claim 3, wherein the tumor is a medulloblastoma.

6. The method of claim 3, wherein the tumor is a meningioma.

7. The method of claim 3, wherein the tumor is a neurofibrosarcoma.

8. The method of claim 1, wherein said mutated herpes simplex virus is R3616.

27. The method of claim 1 wherein the tumor is a glioblastoma.

28. The method of claim 27, wherein the tumor is a medulloblastoma.

29. The method of claim 27, wherein the tumor is a meningioma.

30. The method of claim 27, wherein the tumor is a neurofibrosarcoma.

9. A method for inhibiting growth of nervous system tumor cells, said method comprising:

a) infecting said tumor cells with a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the γ

-34.5 gene; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells, and wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) inhibiting growth of said nervous system tumor cells.

10. The method of claim 9 wherein the tumor is selected from the group consisting of glioblastoma, medulloblastoma, meningioma, neurofibrosarcoma, astrocytoma, oligodendroglioma, neurofibroma, ependymoma and Schwannoma.

11. The method of claim 9, wherein said mutated herpes simplex virus is R3616.

12. A method for selectively killing nervous system tumor cells in a mammal, said method comprising:

a) directly administering to a tumor in said animal a mutated herpes simplex virus, wherein said mutated herpes simplex virus is an intertypic HSV-1 and HSV-2 recombinant with a lesion conferring attenuation mapping to the inverted repeat in the long segment of the HSV genome; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells; and

wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) killing said nervous sytem tumor cells.

13. The method of claim 12, wherein the intertypic recombinant is RE6.

14. The method of claim 12, wherein said mammal is human.

15. The method of claim 12, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

16. The method of claim 15, wherein the tumor is a glioblastoma.

17. The method of claim 15, wherein the tumor is a medulloblastoma.

18. The method of claim 15, wherein the tumor is a meningioma.

19. The method of claim 15, wherein the tumor is a neurofibrosarcoma.

20. A method for inhibiting growth of nervous system tumor cells, said method comprising:

a) infecting said tumor cells with a mutated herpes simplex virus, wherein said mutated herpes simplex virus is an intertypic HSV-1 and HSV-2 recombinant with a lesion conferring attenuation mapping to the inverted repeat in the long segment of the HSV genome; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells, and wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) inhibiting growth of said nervous system tumor cells.

21. The method of claim 20, wherein the intertypic recombinant is RE6.

22. The method of claim 20, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

23. A method for selectively killing nervous system tumor cells in a mammal, said method comprising:

a) directly administering to a tumor in said mammal a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the thymidine kinase gene, wherein said mutation does not impair UL24 gene function; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells; and

wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) killing said nervous system tumor cells.

24. The method of claim 23, wherein said mutated herpes simplex virus is dlsptk.

25. The method of claim 23, wherein said mammal is human.

26. The method of claim 23, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

31. A method for inhibiting growth of nervous system tumor cells, said method comprising:

a) infecting said tumor cells with a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the thymidine kinase gene, wherein said mutation does not impair UL24 gene function; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells, and wherein said mutated herpes virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) inhibiting growth of said nervous system tumor cells.

32. The method of claim 31, wherein said mutated herpes simplex virus is dlsptk.

33. The method of claim 31, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

34. A method for selectively killing nervous system tumor cells in a mammal, said method comprising:

a) directly administering to a tumor in said mammal a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the DNA polymerase gene; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells; and

wherein said mutated herpes simplex virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) killing said nervous system tumor cells.

35. The method of claim 34, wherein said mutated herpes simplex virus is AraA^r13.

36. The method of claim 34, wherein said mammal is human.

37. The method of claim 34, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.

38. The method of claim 37, wherein the tumor is a glioblastoma.

39. The method of claim 37, wherein the tumor is a medulloblastoma.

40. The method of claim 37, wherein the tumor is a meningioma.

41. The method of claim 37, wherein the tumor is a neurofibrosarcoma.

42. A method for inhibiting growth of nervous system tumor cells, said method comprising:

a) infecting said tumor cells with a mutated herpes simplex virus, wherein said mutated herpes simplex virus comprises a mutation in the DNA polymerase gene; and

wherein said mutated herpes simplex virus exhibits decreased virulence in normal neural cells while maintaining cytopathic effects in said nervous system tumor cells, and wherein said mutated herpes virus is capable of selective replication in said nervous system tumor cells; and

thereby

b) inhibiting growth of said nervous system tumor cells.

43. The method of claim 42, wherein said mutated herpes simplex virus is AraA^r13.

44. The method of claim 42, wherein the tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma.