Treatment of cancer using tlr3 agonists

Abstract

The present invention relates generally to the fields of genetics and medicine. More specifically, the present invention relates to improved methods of treating cancers using a TLR3 agonist, by assessing the expression of a TLR3 receptor by cancer cells.

1 . A method for treating a subject having a cancer comprising:
 a. determining whether cancer cells in said subject express a TLR3 receptor, the expression of a TLR3 receptor being indicative of a subject responding to a TLR3 agonist, and   b. administering to said subject whose cancer cells are determined to express a TLR3 receptor a pharmaceutical composition comprising an effective amount of a TLR3 agonist and a pharmaceutically acceptable carrier.   
     
     
         2 . The method according to  claim 1 , wherein said cancer in said subject comprises at least 10% of cancer cells expressing a TLR3 receptor. 
     
     
         3 . The method according to  claim 1 , wherein said TLR3 agonist is a dsRNA TLR agonist. 
     
     
         4 . The method according to  claim 3 , wherein said TLR3 agonist is an siRNA or an shRNA that specifically binds to mRNA encoding a tumor antigen or another protein involved in tumor proliferation. 
     
     
         5 . The method according to  claim 1 , wherein said TLR3 agonist is an antibody or an antigen binding fragment thereof. 
     
     
         6 . The method according to  claim 1 , wherein said determining whether cells of said cancer in said subject express a TLR3 receptor is performed ex vivo on a biopsied sample of said cancer using a TLR3-specific ligand. 
     
     
         7 . The method according to  claim 5 , wherein said TLR3-specific ligand is capable of detecting TLR3 expressed on the surface and in the cytoplasm of cancer cells. 
     
     
         8 . The method according to  claim 5 , wherein said TLR3-specific ligand is an antibody or an antigen binding fragment thereof. 
     
     
         9 . A method for treating a subject having a cancer, the method comprising the steps of:
 a. administering to said subject an effective amount of an agent that causes upregulation of TLR3 expression, and   b. administering to said subject an effective amount of a TLR3 agonist.   
     
     
         10 . The method according to  claim 9 , comprising the additional step of determining whether cells of said cancer in said subject express a TLR3 receptor, said additional step being performed prior to step b. 
     
     
         11 . The method according to  claim 1 , comprising the additional step of administering to said subject a second therapeutic agent selected from a TLR3 agonist of different molecular composition than the TLR3 agonist administered in step b; a cytotoxin; a cytotoxin-TLR3 ligand complex; an agent that inhibits expression or an activity of a tumor antigen; an agent that inhibits expression or an activity of a tumor proliferative protein; a chemotherapy agent, an agent or combination of agents typically used for the treatment of the specific cancer to be treated; an immunostimulatory agent; an immunosuppression agent; a cytokine or cytokine analog; a chemokine; an agent that affects upregulation of a cell surface receptor; an agent that affects GAP junctions; a cytostatic agent; an agent that inhibits differentiation; or an agent that inhibits cell adhesion, wherein said second therapeutic agent is administered separately as part of a multiple dosage regimen, or as part of said pharmaceutical composition. 
     
     
         12 . The method according to  claim 14 , wherein said immunostimulatory agent is IFNα. 
     
     
         13 . A pharmaceutical composition comprising:
 a. a TLR3 agonist;   b. a second therapeutic agent selected from a second TLR3 agonist TLR3 agonist different from the TLR3 agonist of a; a cytotoxin; a cytotoxin-TLR3 ligand complex; an agent that inhibits expression or an activity of a tumor antigen; an agent that inhibits expression or an activity of a tumor proliferative protein; a chemotherapy agent; an agent or combination of agents typically used for the treatment of the specific cancer to be treated; an immunostimulatory agent; an immunosuppression agent; a cytokine or cytokine analog; a chemokines, an agent that affects upregulation of a cell surface receptor; an agent that affects GAP junctions; a cytostatic agent; an agent that inhibits differentiation; an agent that inhibits cell adhesion; or an endocytosis inhibitor; and   c. a pharmaceutically acceptable carrier.   
     
     
         14 . The composition according to  claim 13  wherein the active ingredients of said composition are in separate dosage forms. 
     
     
         15 . An implantable drug release device impregnated with or containing a TLR3 agonist or a composition comprising a TLR3 agonist, such that said TLR3 agonist is released from said device and is therapeutically active. 
     
     
         16 . A kit comprising:
 a. a cancer cell or cancer cell line that expresses TLR3;   b. a TLR3-specific ligand; and   c. a reagent for detecting the binding of said TLR3-specific ligand to a TLR3 expressed by said cancer cell wherein said kit is for determining if an agent is capable of increasing the susceptibility of a cancer to treatment with a TLR3 agonist; or   a. a TLR3-specific ligand; and   b. additional reagents for detecting the expression of a TLR3 receptor in a cancer cell in a sample, wherein said kit is for assessing the response of a subject having cancer to a treatment using a TLR3 agonist or for selecting subjects having a cancer that responds to a treatment using a TLR3 agonist; or   a. reagents for determining the expression of a TLR3 receptor in a cancer cell in a sample;   b. a cancer cell characterized by the presence of TLR3 on its cell surface and a reagent for detecting if said test compound causes TLR3-mediated apoptosis or cell death of said cancer cell; and   c. optionally comprising a reagent that detects agonism of TLR3 by said test compound, wherein said kit is for determining if a test compound is useful for the treatment of cancer.   
     
     
         17 . The kit according to  claim 16 , wherein the TLR3-specific ligand selected from an antibody or a fragment or a derivative thereof; a TLR3-specific nucleic acid primer or probe; or a double-stranded RNA molecule. 
     
     
         18 . A complex comprising:
 a. a TLR3 ligand; and   b. a cytotoxic agent, wherein said agonist and said cytotoxic agent are bound to one another directly through a covalent bond, bond to one another through a non-covalent bond, conjugated to one another directly or through a linking moiety or are present in a single pharmaceutical carrier or vehicle.   
     
     
         19 . The complex according to  claim 18 , wherein said TLR3 ligand is selected from an antibody, or a fragment or derivative thereof, that specifically binds to TLR3; or a double-stranded RNA molecule. 
     
     
         20 . A method for assessing the response of a subject having cancer to a treatment using a TLR3 agonist or selecting a subject having a cancer that responds to a treatment using a TLR3 agonist, the method comprising the step of determining whether cancer cells in said subject express a TLR3 receptor, the expression of a TLR3 receptor being indicative of a responder subject. 
     
     
         21 . A method of determining if a test compound is useful for the treatment of cancer, said method comprising the step of determining if said test compound is a TLR3 agonist. 
     
     
         22 . The method according to  claim 21 , wherein said determining if a test compound is useful for the treatment of cancer comprises the steps of:
 a. contacting said test compound with a cancer cell characterized by the presence of TLR3 on its cell surface; and   b. determining if said test compound induces a TLR3-mediated biological effect.   
     
     
         23 . A method for assessing the response of a subject having cancer to a treatment using a TLR3 agonist, the method comprising determining whether cancer cells in said subject express a TLR3 receptor, the expression of a TLR3 receptor being indicative of a responder subject. 
     
     
         24 . A method for selecting subjects having a cancer that respond to a treatment using a TLR3 agonist, the method comprising determining whether cancer cells in said subject express a TLR3 receptor, the expression of a TLR3 receptor being indicative of a responder subject. 
     
     
         25 . A method for treating a subject having a cancer, the method comprising determining whether cancer cells in said subject express a TLR3 receptor, the expression of a TLR3 receptor being indicative of a subject responding to a TLR3 agonist, and treating said subject whose cancer cells express a TLR3 receptor with a TLR3 agonist.