Methods and Compositions for Treatment of Interferon-Resistant Tumors

Abstract

The present invention provides a method for the treatment of “interferon resistant” tumors (i.e., tumors resistant to treatment with exogenously-administered interferon polypeptide) through the use of a non-replicating agent which induces human cells to express interferon species. In particular it is noted that inducing interferon expression in the patient's body possesses properties not associated with exogenously-produced intravenously-administered interferon proteins. The present invention further provides compositions useful in the treatment of cancer resistant to treatment with exogenous interferon polypeptide, by using a non-replicating agent which induces human cells to express interferon species, e.g., an antigenic, replication-deficient virus optionally carrying an interferon transgene.

1 . A method of treating a human with non-muscle invasive bladder cancer resistant to or recurrent after Bacillus Calmette-Guérin instillation, comprising:
 a. Diagnosing in a human non-muscle invasive bladder cancer resistant to or recurrent after Bacillus Calmette-Guérin instillation, and then 
 b. Administering by instillation to the lumen of the bladder of said human a replication-deficient adenovirus, said adenovirus comprising an expressible transgene, said adenovirus able to induce endogenous interferon expression, said adenovirus administered in an amount effective to treat said non-muscle invasive bladder cancer. 
 
     
     
         2 . The method of  claim 1 , where said amount effective to treat said non-muscle invasive bladder cancer comprises an amount effective to induce expression of eIF2 or RNAse L. 
     
     
         3 . The method of  claim 1 , where the amount effective to treat said non-muscle invasive bladder cancer comprises an amount effective to increase the presentation of cancer antigen to T cells. 
     
     
         4 . The method of  claim 1 , further comprising administering transfection enhancer by instillation to the lumen of the bladder. 
     
     
         5 . The method of  claim 4 , said adenovirus administered as a non-emulsified suspension. 
     
     
         6 . The method of  claim 5 , wherein said surfactant is administered before said adenovirus is administered. 
     
     
         7 . The method of  claim 1 , said adenovirus administered as a non-emulsified suspension. 
     
     
         8 . The method of  claim 4 , wherein said transfection enhancer comprises N-[3-[(4-O-D-galactopyranosyl-D-glucanoyl)amino]propyl]-3,7,12-trihydroxy-N-[3-[[(3α, 5β, 7α, 12α)-3,7,12-trihydroxy-24-oxocholan-24-yl]amino]propyl]-(3α, 5β, 7α, 12α)-cholan-24-amide. 
     
     
         9 . The method of  claim 1 , further comprising administering a checkpoint inhibitor. 
     
     
         10 . A method of treating a human with non-muscle invasive bladder cancer resistant to or recurrent after treatment with BCG, the method comprising:
 a. diagnosing a human with non-muscle invasive bladder cancer which is resistant to or recurrent after treatment with BCG, and then   b. administering to said human by instillation into the bladder lumen
 i. a replication-deficient vector comprising an expressible transgene which codes for a polypeptide which inhibits protein synthesis in cancer cells, and 
 ii. a transfection enhancer, the transfection enhancer administered in an amount effective to increase expression of the transgene compared to administration of said transgene to intact bladder lumen without said enhancer, 
   c. said expressible transgene and said transfection enhancer administered in an amount effective to express said polypeptide in an amount effective to treat said cancer.   
     
     
         11 . The method of  claim 10 , where the polypeptide which inhibits protein synthesis in cancer cells comprises a polypeptide selected from the group consisting of: eIF2 and RNAse L. 
     
     
         12 . The method of  claim 10 , wherein said transfection enhancer comprises N-[3-[(4-O-D-galactopyranosyl-D-glucanoyl)amino]propyl]-3,7,12-trihydroxy-N-[3-[[(3α, 5β, 7α, 12α)-3,7,12-trihydroxy-24-oxocholan-24-yl]amino]propyl]-(3α, 5β, 7α, 12α)-cholan-24-amide. 
     
     
         13 . The method of  claim 10 , further comprising administering a checkpoint inhibitor. 
     
     
         14 . A method of treating non-muscle invasive bladder cancer comprising:
 a. diagnosing in a human non-muscle invasive bladder cancer resistant to or recurrent after Bacille Calmette-Guérin instillation therapy, and then   b. administering to the human by instillation into the human's bladder lumen a non-interferon agent which induces endogenous interferon expression in human cells which are exposed to it,
 i. said agent being replication-deficient, 
 ii. said agent formulated in normal saline as a non-emulsified suspension suitable for intravesical irrigation, 
 iii. said formulation providing said agent in an amount sufficient to induce interferon production in human bladder cells, 
 iv. said formulation further providing said agent in an amount effective to treat non-muscle invasive bladder cancer resistant to or recurrent after Bacille Calmette-Guérin instillation therapy. 
   
     
     
         15 . The method of  claim 14 , wherein said replication-deficient agent is antigenic. 
     
     
         16 . The method of  claim 15 , said antigenic agent comprising adenovirus. 
     
     
         17 . The method of  claim 16  wherein said adenovirus comprises an expressible interferon transgene. 
     
     
         18 . The method of  claim 17 , further comprising administering a transfection enhancer. 
     
     
         19 . The method of  claim 14 , further comprising administering a checkpoint inhibitor.