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 TLR3 receptor by cancer cells.

1 - 49 . (canceled) 
     
     
         50 . A method for treating a subject having a cancer, the method comprising the steps of:
 a. determining whether cells of said cancer 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.   
     
     
         51 . The method according to  claim 50 , wherein said TLR3 agonist is a dsRNA TLR3 agonist. 
     
     
         52 . The method according to  claim 51 , wherein said dsRNA TLR3 agonist is at least 90% double-stranded. 
     
     
         53 . The method according to  claim 52 , wherein said dsRNA TLR3 agonist is selected from polyA:polyU, polyI:polyC, or polyI:poly(C 12 U). 
     
     
         54 . The method according to  claim 53 , wherein said dsRNA is a fully double stranded polyA:polyU molecule consisting of between 19 and 30 base pairs and comprising between 1 and 30 stabilizing modifications, or a 3′ cap, or a 5′ cap. 
     
     
         55 . The method according to  claim 50 , wherein said cancer is selected from a solid tumor or a carcinoma. 
     
     
         56 . The method according to  claim 55 , wherein the solid tumor is selected from breast cancer, colon cancer, lung cancer, renal cancer, metastatic or invasive malignant melanoma, prostate cancer, brain tumor, bladder cancer and liver cancer. 
     
     
         57 . The method according to  claim 56 , wherein said solid tumor is a breast cancer. 
     
     
         58 . The method according to  claim 57 , wherein said breast cancer is a lymph node-positive breast cancer involving 1 to 3 lymph nodes. 
     
     
         59 . The method according to  claim 50 , 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. 
     
     
         60 . The method according to  claim 59 , wherein said TLR3-specific ligand is an antibody or a fragment or a derivative thereof. 
     
     
         61 . The method according to  claim 59 , wherein said TLR3-specific ligand is a TLR3-specific nucleic acid primer or probe. 
     
     
         62 . The method according to  claim 55  comprising the additional step of surgically removing a portion of said solid tumor prior to administering said TLR3 agonist. 
     
     
         63 . The method according to  claim 50 , wherein said subject is administered said TLR3 agonist about once every week for at least about six weeks. 
     
     
         64 . The method according to  claim 50 , further comprising 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 immunsuppression 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, 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. 
     
     
         65 . The method according to  claim 50 , additionally comprising treating said subject with radiotherapy. 
     
     
         66 . The method according to  claim 62 , wherein said TLR3 agonist composition is formulated into an implantable drug release device that is implanted near the site of said solid tumor during said surgical procedure. 
     
     
         67 . The method according to  claim 52 , wherein said dsTLR3 agonist is an siRNA or an shRNA that specifically binds to mRNA encoding a tumor antigen or another protein involved in tumor proliferation. 
     
     
         68 . A method for treating a subject having a cancer, the method comprising the steps of:
 administering to said subject an effective amount of an agent that causes upregulation of TLR3 expression, and   administering to said subject an effective amount of a TLR3 agonist.   
     
     
         69 . The method according to  claim 68 , 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. 
     
     
         70 . A composition of matter for treating a subject having a cancer comprising, in separate dosage forms:
 a. an agent that causes upregulation of TLR3 expression, and   b. a TLR3 agonist,   
       wherein said agent and said agonist are associated with one another in said composition of matter. 
     
     
         71 . A kit for determining if an agent is capable of increasing the susceptibility of a cancer to treatment with a TLR3 agonist, wherein the kit comprises:
 a. a cancer cell or cancer cell line which can express 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.   
     
     
         72 . A pharmaceutical composition comprising:
 a. a TLR3 agonist;   b. a second therapeutic agent selected from a TLR3 agonist of different molecular composition the TLR3 agonist of part 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 immunsuppression 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.   
     
     
         73 . A composition of matter for treating a subject having a cancer comprising, in separate dosage forms:
 a. a TLR3 agonist; and   b. a second therapeutic agent selected from a TLR3 agonist of different molecular composition the TLR3 agonist of part 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, a TLR2, TLR4, TLR7, TLR8 or TLR9 agonist, an immunsuppression 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, a pro-apoptotic agent, an agent that inhibits differentiation, an agent that inhibits cell adhesion, or an endocytosis inhibitor,   
       wherein said agent and said agonist are associated with one another in said composition of matter. 
     
     
         74 . A method of impregnating or filling an implantable drug release device comprising the step of contacting said drug release device with a TLR3 agonist or a composition comprising a TLR3 agonist. 
     
     
         75 . 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. 
     
     
         76 . 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. 
     
     
         77 . A kit 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, the kit comprising:
 a. a TLR3-specific ligand; and   b. additional reagents for detecting the expression of a TLR3 receptor in a cancer cell in a sample.   
     
     
         78 . The kit according to  claim 77 , 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. 
     
     
         79 . 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. 
     
     
         80 . The complex according to  claim 79 , 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. 
     
     
         81 . 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. 
     
     
         82 . The method according to  claim 81 , 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.   
     
     
         83 . The method according to  claim 82 , wherein said TLR3-mediated biological effect is apoptosis or cell death of said cancer cell. 
     
     
         84 . A kit for determining if a test compound is useful for the treatment of cancer, said kit comprising:
 a. a cancer cell characterized by the presence of TLR3 on its cell surface; and   b. a reagent for detecting if said test compound causes TLR3-mediated apoptosis or cell death of said cancer cell; and   optionally comprising a reagent that detects agonism of TLR3 by said test compound.