Systemic Treatment of Metastatic and/or Systemically-Disseminated Cancers using GM-CSF-Expressing Poxviruses

Abstract

The present invention concerns methods and compositions for the treatment of cancer and cancer cells using intravascular administration of a vaccinia virus. In some embodiments, methods and compositions involve a replicative vaccinia virus that encodes GM-CSF.

1 . A method of killing a cancer cell in a subject comprising administering to the subject an effective amount of a replicative vaccinia virus having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular. 
   
   
       2 . The method of  claim 1 , wherein the vaccinia virus is administered intravenously. 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . The method of  claim 1 , wherein the vaccinia virus has a deletion in its genome. 
   
   
       6 . The method of  claim 5 , wherein the vaccinia virus has a mutation in one or more genes. 
   
   
       7 . (canceled) 
   
   
       8 . The method of  claim 6 , wherein at least the thymidine kinase gene has been deleted. 
   
   
       9 . The method of  claim 6 , wherein the vaccinia virus has a mutation in a gene encoding:
 a) vaccinia virus growth factor;   b) a functional interferon-modulating polypeptide, wherein the interferon-modulating polypeptide directly binds interferon;   c) a complement control polypeptide, wherein the mutation results in the virus lacking at least one functional complement control polypeptide;   d) a TNF-modulating polypeptide, wherein the mutation results in the virus lacking at least one functional TNF-modulating polypeptide;   e) a serine protease inhibitor, wherein the mutation results in the virus lacking at least one functional serine protease inhibitor;   f) an IL-1β modulator polypeptide, wherein the mutation results in the virus lacking at least one functional IL-1β modulator polypeptide;   g) a functional A41L, B7R, N1L or vCKBP chemokine binding polypeptide or C11R EGF-like polypeptide, wherein the mutation results in the virus lacking at least one function of A41L, B7R, NIL, vCKBP, or C11R; or   h) a polypeptide, wherein the mutation results in an increase in infectious EEV form of vaccinia virus.   
   
   
       10 . The method of  claim 8 , further comprising a mutation in a vaccinia virus growth factor. 
   
   
       11 . The method of  claim 1 , wherein the vaccinia virus is the Wyeth or Western Reserve (WR) strain. 
   
   
       12 . (canceled) 
   
   
       13 . The method of  claim 1 , wherein the promoter is a vaccinia virus promoter or a synthetic promoter. 
   
   
       14 . (canceled) 
   
   
       15 . The method of  claim 13 , wherein the promoter directs transcription during at least the early phase of infection. 
   
   
       16 . The method of  claim 13 , wherein the promoter directs transcription during at least the late phase of infection. 
   
   
       17 . The method of  claim 1 , wherein the subject is administered the vaccinia virus multiple times. 
   
   
       18 . (canceled) 
   
   
       19 . (canceled) 
   
   
       20 . (canceled) 
   
   
       21 . The method of  claim 1 , wherein the subject is administered between about 10 5  and about 10 13  pfu of virus. 
   
   
       22 . (canceled) 
   
   
       23 . The method of  claim 1 , wherein the administration occurs intravascularly by injection. 
   
   
       24 . The method of  claim 1 , wherein the administration occurs intravascularly using intravenous drip or bolus. 
   
   
       25 . The method of  claim 1 , wherein the administration occurs intravascularly using a pump. 
   
   
       26 . The method of  claim 1 , wherein the cancer cell is a metastasized cancer cell. 
   
   
       27 . The method of  claim 1 , wherein the subject has lung cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, hepatocellular cancer, leukemia, lymphoma, myeloma, or melanoma. 
   
   
       28 . A method for treating cancer in a subject comprising administering to the subject an effective amount of a replicative vaccinia virus having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular. 
   
   
       29 . A method for treating one or more metastases in a subject comprising administering to the subject an effective amount of a replicative vaccinia having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular.