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1. WO2013158265 - IMAGING METHODS FOR ONCOLYTIC VIRUS THERAPY

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[ EN ]

CLAIMS:

1. A method for detecting or imaging tissues infected by an oncolytic virus, comprising:

administering an oncolytic virus to a subject;

administering an agent for detection of macrophages or inflammatory cells in a subject;

detecting or imaging the accumulation of macrophages or inflammatory cells in a subject, wherein accumulation of the agent in tissues comprising macrophages or inflammatory cells indicates that the oncolytic virus has infected tissues comprising the macrophage or inflammatory cells, thereby detecting or imaging the cells infected by the oncolytic virus.

2. The method of claim 1, wherein the agent detects macrophages.

3. The method of claim 1, wherein:

the subject has a tumor; and

detection of the macrophages or inflammatory cells detects or images cells infected by the oncolytic virus, thereby detecting or imaging tumor cells or tissue in the subject.

4. The method of claim 1, wherein oncolytic therapy is monitored by periodically imaging or detecting the macrophages to detect or image changes in the profile of accumulated macrophages and thereby monitor therapy.

5. The method of any of claims 1-4, wherein the oncolytic virus does not encode any heterologous proteins for detection of the virus or heterologous proteins that induce a detectable signal.

6. The method of any of claims 1-4, wherein the virus is a clonal strain of a virus so that it does not encode any heterologous non-viral gene products.

7. The method of any of claims 1-5, wherein the virus encodes a therapeutic protein.

8. The method of claim 7, wherein the therapeutic protein is a protein for treating tumors.

9. The method of claim 4, wherein monitoring assesses whether the therapy is effective by detecting an increase in infected cells within a predetermined time after administration of the virus, wherein the time is sufficient for the oncolytic virus to infect tumor cells.

10. The method of claim 1, wherein the subject has a tumor or tumors, and is administered oncolytic therapy for treatment of the tumors.

11. The method of claim 9, wherein the predetermined time is less than 24 days.

12. The method of any of claims 1-11, wherein the agent for detection of macrophage or inflammatory cells is an imaging agent containing a perfluorocarbon.

13. The method of any of claims 1-12, wherein accumulation of the agent in the tumor is indicative that the oncolytic virus treatment is or will be efficacious.

14. The method of any of claims 1-12, wherein accumulation of the agent in the tumor indicates that the oncolytic virus is a candidate for treatment of the tumor.

15. The method of any of claims 1-12, wherein accumulation of the agent in the tumor indicates that the subject is a candidate for treatment of the tumor with oncolytic virus.

16. The method of any of claims 1-15, wherein the agent is detected or imaged in vivo in the subject.

17. The method of any of claims 1-15, wherein the agent is detected or imaged ex vivo in a tumor biopsy sample from the subject.

18. The method of any of claims 1-15, further comprising obtaining a tumor biopsy sample from the subject.

19. The method of claim 18, wherein the tumor biopsy is from a solid tumor.

20. The method of any of claims 1-19, wherein the agent is detected or imaged by magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS).

21. The method of any of claims 1-20, wherein the imaging agent is administered at a predetermined time prior to the administration of the oncolytic virus.

22. The method of any of claims 1-21 , wherein the agent is administered 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, or 48 hours prior to the administration of the oncolytic virus.

23. The method of any of claims 1-20, wherein the agent is administered at a predetermined time following the administration of the oncolytic virus.

24. The method of any of claims 1-24, wherein the agent is administered

1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, 2 days,3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks 4 weeks, 1 month following the administration of the oncolytic virus.

25. The method of any of claims 1-20, wherein the agent is administered at the same time as the oncolytic virus or sequentially or intermittently with the virus.

26. The method of any of claims 1-20, wherein the agent and the oncolytic virus are administered in the same composition or in separate compositions.

27. The method of any of claims 1-26, wherein the agent is detected or imaged at least lhour, 2 hours, 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours following the administration of the imaging agent.

28. The method of any of claims 1-27, wherein the agent is detected or imaged at a plurality of times at successive time points following administration of the oncolytic virus.

29. The method of any of claims 1-28, wherein:

the oncolytic virus is administered in an amount sufficient to induce accumulation of the agent; and

the amount is lower than a treatment dosage of the virus.

30. The method of any of claims 1-28, wherein the oncolytic virus is

2 8

administered at a dosage selected from among 1 x 10 pfu to 1 x 10 pfu, or is administered in an amount that is at least or at least about or is or is about 1 x 10 pfu, 1 x 103 pfu, 1 x 104 pfu, 1 x 105 pfu, 1 106 pfu, 1 107 pfu or 1 χ 108 pfu.

31. The method of any of claims 1-28, wherein the virus is administered at a dosage for treatment of a tumor or cancer.

32. The method of any of claims 1-28, wherein the virus is administered at a dosage selected from among 1 x 106 pfu to 1 x 1014 pfu, or is administered in an

amount that is at least or at least about or is or is about 1 χ 106 pfu, 1 x 107 pfu or 1 χ 108 pfu, 1 x 109 pfu, 1 x 10,o pfu, 1 10n pfu, 1 1012 pfu, 1 x 10I3 pfu, or 1 χ 1014 pfu.

33. The method of any of claims 1-32, wherein if the treatment is efficacious, continuing treatment of the subject by administering the oncolytic virus for treatment.

34. The method of any of claims 1-33, wherein the agent is administered intravenously.

35. The method of any of claims 1-34, wherein the oncolytic virus is administered systemically.

36. The method of claim 35, wherein the oncolytic virus is administered by intravenous, intraarterial, intratumoral, endoscopic, intralesional, intramuscular, intraperitoneal, intradermal, intravesicular, intraarticular, intrapleural, percutaneous,' subcutaneous, oral, parenteral, intranasal, intratracheal, inhalation, intracranial, intraprostatic, intravitreal, topical, ocular, vaginal, or a rectal route of administration.

37. The method of any of claims 1-36, wherein the virus is administered a plurality of times and the agent is detected or imaged at a predetermined time after each successive administration of the virus in a cycle of administration.

38. The method of any of claims 1-37, wherein the oncolytic virus is administered in an amount that is at least 1 109 pfu at least one time over at least one cycle of administration.

39. 1 The method of any of claims 1-38, wherein the virus is administered for a plurality of cycles and the cycle of administration is at least or is two days, three days, four days, five days, six days, seven days, 14 days, 21 days or 28 days.

40. The method of claim 38 or claim 39, wherein the amount of vims is administered two times, three times, four times, five times, six times or seven times over the cycle of administration.

41. The method of any of claims 38-40, wherein the amount of virus is administered on the first day of the cycle, the first and second day of the cycle, each of the first three consecutive days of the cycle, each of the first four consecutive days of the cycle, each of the first five consecutive days of the cycle, each of the first six consecutive days of the cycle, or each of the first seven consecutive days of the cycle.

42. The method of any of claims 1-41, wherein the agent is a

perflurocarbon imaging agent that is selected from among a linear perf uorocarbon, a branched perfluorocarbon, and a cyclic perfluorocarbon.

43. The method of any of claims 1-41, wherein agent is a perflurocarbon imaging agent that contains a perflurocarbon selected from among a

perfluoropolyether, perfiuoro crown ether, perfluoroalkane, perf uoropentane, perfluorohexane, perf uorononane, perfluorohexyl bromide, perfluorooctyl bromide, perfiuorooctane, perf uorodecalin, perfiuorocycloalkane, perfiuoro amine, and mixtures thereof.

44. The method of any of claims 1-43, wherein the agent is a

perflurocarbon imaging agent that contains two or more perfluorocarbons.

45. The method of any of claims 1-43, wherein the agent is a

perflurocarbon imaging agent that is a perf uoroalkyl ether.

46. The method of any of claims 1-43, wherein the agent is a

perflurocarbon imaging agent that is perfiuoro- 15 -crown-5 -ether.

47. The method of any of claims 1-43, wherein the agent accumulates in macrophages by phagocytosis.

48. The method of any of claims 1-43, wherein the agent is a

perflurocarbon imaging agent that contains a poly(ethylene oxide) block copolymer.

49. The method of claim 48, wherein the poly(ethylene oxide) block copolymer is a poly(ethylene oxide)-polyester block copolymer.

50. The method of claim 49, wherein the poly(ethylene oxide) block copolymer is selected from among poly(ethylene oxide)-block-poly(8-caprolactone) copolymer, poly(ethylene oxide)-block-(L) polylactide copolymer, poly(ethylene oxide)-block-(D) polylactide copolymer, poly(ethylene oxide)-block-(D,L) polylactide copolymer, and combinations thereof.

51. The method of claim 49, wherein the poly(ethylene oxide) block copolymer is a poly(ethylene oxide)-polyether block copolymer or is a polyethylene-polyether tri-block copolymer or is a poly(ethylene oxide)- poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer.

52. The method of any of claims 1-51, wherein the agent is formulated as an emulsion.

53. The method of claim 52, wherein the agent is present in the emulsion in an amount of from about 5% v/v to about 60% v/v, inclusive, of the emulsion.

54. The method of claim 52, wherein the perfluorocarbon is present in the emulsion from about 10% v/v to about 40% v/v of the emulsion.

55. The method of claim 52, wherein the emulsion comprises nanoparticles with an average size of less than or about 800 nm.

56. The method of claim 55, wherein the emulsion comprises nanoparticles with an average size of less than or about 500 nm.

57. The method of any of claims 52-56, wherein the emulsion has a polydispersity index ranging from about 0.1 to about 0.2.

58. The method of any of claims 1-57, wherein the agent contains a targeting moiety targeting it to macrophage and/or other inflammatory cells and/ or a detectable moiety.

59. The method of claim 58, wherein the detectable moiety is a dye or a fluorescent molecule.

60. The method of any of claims 1-59, wherein the agent is a

perfluorocarbon that comprises an 18 F isotope.

18

61. The method of claim 60, wherein the F isotope can be imaged by positron emission tomography (PET) imaging

62. The method of any of claims 1-62, wherein the subject is a mammal.

63. The method of any of claims 1-62, wherein the subject is a human.

64. The method of any of claims 1-62, wherein the subject is a non-human animal.

65. The method of claim 64, wherein the subject is a domesticated or farm animal.

66. The method of claim 64, wherein the subject is an ape, monkey, gorilla, mouse, rat, rabbit, ferret, chicken, goat, cow, deer, sheep, horse, pig, dog, or cat.

67. The method of any of claims 1-66, wherein the subject has a tumor of the lung, breast, colon, brain, prostate, liver, pancreas, esophagus, kidney, stomach, thyroid, bladder, uterus, cervix or ovary.

68. The method of any of claims 1-67, wherein the tumor is a metastatic tumor.

69. The method of any of claims 1-68, wherein the oncolytic virus is a vaccinia virus.

70. The method of any of claims 1-68, wherein the oncolytic virus is a Lister strain virus or a Wyeth strain virus.

71. The method of any of claims 1-68, wherein the virus is an LIVP virus.

72. The method of any of claims 1-68, wherein the virus is an LIVP virus or modified form thereof and the virus comprises a sequence of nucleotides set forth in SEQ ID NO:2, or a sequence of nucleotides that has at least 95 % sequence identity to SEQ ID NO:2.

73. The method of any of claims 1-68, wherein the virus is a clonal strain of LIVP or a modified form thereof comprising a sequence of nucleotides selected from:

a) nucleotides 2,256 - 181,114 of SEQ ID NO:20, nucleotides 11,243 -182,721 of SEQ ID NO:21, nucleotides 6,264 - 181,390 of SEQ ID NO:22, nucleotides 7,044 - 181,820 of SEQ ID NO:23, nucleotides 6,674 - 181,409 of SEQ ID NO:24, nucleotides 6,716 - 181,367 of SEQ ID NO:25 or nucleotides 6,899 -181,870 of SEQ ID NO:26;

b) a sequence of nucleotides that has at least 97% sequence identity to a sequence of nucleotides 2,256 - 181,114 of SEQ ID NO:20, nucleotides 1 1,243 -182,721 of SEQ ID NO:21, nucleotides 6,264 - 181,390 of SEQ ID NO:22, nucleotides 7,044 - 181,820 of SEQ ID NO:23, nucleotides 6,674 - 181,409 of SEQ ID NO:24, nucleotides 6,716 - 181,367 of SEQ ID NO:25 or nucleotides 6,899 -181,870 of SEQ ID NO:26;

c) a sequence of nucleotides set forth in SEQ ID NOS: 20-26; or

d) a sequence of nucleotides that has at least 97% sequence identity to a sequence of nucleotides set forth in SEQ ID NO: 20-26.

74. The method of any of claims 1-68, wherein the oncolytic virus, comprises the sequence of nucleotides set forth in SEQ ID NO: 1 , or a sequence of nucleotides that exhibits at least 99% sequence identity to SEQ ID NO: 1 or is the virus designated GLV- 1 h68 or a derivative thereof.

75. The method of any of claims 1-74, wherein the oncolytic virus comprises nucleic acid encoding a heterologous gene product.

76. The method of claim 75, wherein the nucleic acid encoding the heterologous gene product is inserted into or in place of a non-essential gene or region in the genome of the virus.

77. The method of claim 76, wherein the nucleic acid encoding the heterologous gene product is inserted at the hemagglutinin (HA), thymidine kinase (TK), F14.5L, vaccinia growth factor (VGF), A35R, NIL, E2L/E3L, K1L/K2L, superoxide dismutase locus, 7.5K, C7-K1L, B13R+B14R, A26L or I4L gene loci in the genome of the virus.

78. The method of any of claims 1-77, wherein nucleic acid encoding the heterologous gene product is operatively linked to a promoter.

79. The method of claim 78, wherein the promoter is a constitutive or inducible promoter.

80. The method of any of claims 75-79 wherein the heterologous nucleic acid encodes a reporter gene product.

81. The method of claim 80, wherein the reporter gene product is a fluorescent protein, a bioluminescent protein, a receptor or an enzyme.

82. The method of claim 81 , wherein the fluorescent protein is selected from among a green fluorescent protein, an enhanced green fluorescent protein, a blue fluorescent protein, a cyan fluorescent protein, a yellow fluorescent protein, a red fluorescent protein, and a far-red fluorescent protein.

83. The method of claim 82, where the reporter product is a fluorescent protein is Katushka (TurboFP63 ) from far-red mutant of the red fluorescent protein from sea anemone Entacmaea quadricolor.

84. The method of claim 81 , wherein the reporter product is an enzyme selected from among a luciferase, β-glucuronidase, β-galactosidase, chloramphenicol acetyl tranferase (CAT), alkaline phosphatase, and horseradish peroxidase.

85. The method of claim 81 , wherein the reporter product is an enzyme that is detected by reaction of the enzyme with a substrate.

86. The method of claim 81 , wherein the reporter gene product is a receptor that binds to a detectable moiety or a ligand attached to a detectable moiety.

87. The method of claim 86, wherein the detectable moiety is selected from among a radiolabel, a chromogen, or a fluorescent moiety.

88. The method of any of claims 80-87, further comprising detecting the oncolytic virus by detecting the reporter gene product.

89. The method of claim 88, wherein the oncolytic virus is detected in vivo in the subject or ex vivo in a tumor biopsy sample from the subject.

90. The method of any of claims 80-89, wherein the expression of the reporter gene product is detected by a method selected from among flow cytometry, fluorescence microscopy, fluorescence spectroscopy, magnetic resonance

spectroscopy, positron emission tomography and luminescence spectroscopy.

91. The method of any of claims 1-90, wherein the virus comprises heterologous nucleic acid that encodes a therapeutic or diagnostic agent.

92. The method of claim 91, wherein the heterologous gene product is selected from among an anticancer agent, an antimetastatic agent, an antiangiogenic agent, an immunomodulatory molecule, an antigen, a cell matrix degradative gene, genes for tissue regeneration and reprogramming human somatic cells to

pluripotency, enzymes that modify a substrate to produce a detectable product or signal or are detectable by antibodies, proteins that can bind a contrasting agent, genes for optical imaging or detection, genes for PET imaging and genes for MRI imaging.

93. A combination, comprising:

an oncolytic virus; and

an agent for imaging macrophages.

94. The combination of claim 93, wherein the agent is a perfluorocarbon imaging agent.

95. The combination of claim 93 or 94, wherein the virus is a vaccinia virus.

96. The combination of claim 95, wherein the vaccinia virus is a Lister strain or Wyeth strain virus.

97. The combination of claim 95, wherein the vaccinia virus is an LIVP virus.

98. The combination of any of claims 93-97 that is packaged as a kit.

99. A composition for use for detecting or imaging cells infected with an oncolytic virus, wherein

the composition comprises an agent for detection of inflammatory cell or macrophages; and

detection of the macrophages or inflammatory cells indicates infection of cells by the oncolytic virus to thereby provide for detection or imaging of the cells infected by the virus.

100. The composition of claim 99, wherein the agent is a perfluorocarbon imaging agent.

101. The composition of claim 99 or claim 100, wherein the oncolytic virus is a vaccinia virus.

102. The composition of claim 101, wherein the vaccinia virus is a Lister strain or Wyeth strain virus.

103. The composition of claim 101, wherein the vaccinia virus is an LIVP virus.

104. The composition of any of claims 99-103, wherein the agent is a perflurocarbon imaging agent that is selected from among a linear perfluorocarbon, a branched perfluorocarbon, and a cyclic perfluorocarbon.

105. The composition of any of claims 99-103, wherein agent is a perflurocarbon imaging agent that contains a perflurocarbon selected from among a peril uoropolyether, perfluoro crown ether, perfluoroalkane, perfluoropentane, perfluorohexane, perfluorononane, perfluorohexyl bromide, perfluorooctyl bromide, perfluorooctane, perfluorodecalin, perfluorocycloalkane, perfluoro amine, and mixtures thereof.

106. The composition of any of claims 99- 103, wherein the agent is a perflurocarbon imaging agent that contains two or more perfluorocarbons.

107. The composition of any of claims 99-103, wherein the agent is a perflurocarbon imaging agent that is a perfluoroalkyl ether.

108. The composition of any of claims 99-103, wherein the agent is a perflurocarbon imaging agent that is perfluoro-15-crown-5-ether.

109. The composition of any of claims 99- 103 , wherein the agent accumulates in macrophages by phagocytosis.

1 10. The composition of any of claims 99- 103, wherein the agent is a perflurocarbon imaging agent that contains a poly(ethylene oxide) block copolymer.

1 1 1. The composition of claim 1 10, wherein the poly(ethylene oxide) block copolymer is a poly(ethylene oxide)-polyester block copolymer.

1 12. The composition of claiml 10, wherein the poly(ethylene oxide) block copolymer is selected from among poly(ethylene oxide)-block-poly(e-caprolactone) copolymer, poly(ethylene oxide)-block-(L) polylactide copolymer, poly(ethylene oxide)-block-(D) polylactide copolymer, poly(ethylene oxide)-block-(D,L) polylactide copolymer, and combinations thereof.

1 13. The composition of claim 112, wherein the poly(ethylene oxide) block copolymer is a poly(ethylene oxide)-polyether block copolymer or is a polyethylene-polyether tri-block copolymer or is a poly(ethylene oxide)- poly(propylene oxide)-poIy(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer.

1 14. The composition of any of claims 99-1 13, wherein the agent is formulated as an emulsion.

1 15. The composition of any of claims 99- 114, wherein the agent is formulated for systemic administration.