Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines

Abstract

The present invention relates to synergistic combinations of immunostimulatory CpG oligonucleotides and immunopotentiating cytokines. In particular, the invention relates to methods of stimulating an immune response using the synergistic combination of compounds and products related thereto.

1 - 20 . (canceled)  
     
     
         21 . A method for stimulating an immune response in a subject, comprising: administering to a subject exposed to an antigen an effective amount for inducing a synergistic antigen specific immune response of a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   5′ X 1 CGX 2  3′ 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
       wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X 1  and X 2  are nucleotides, whereby an antigen is optionally additionally administered, and wherein the antigen and the CpG oligonucleotide are not conjugated.  
     
     
         22 . The method of  claim 21 , wherein the Flt3 ligand and the antigen are fused to form an antigen-Flt3 ligand fusion protein.  
     
     
         23 . The method of  claim 21 , wherein the antigen is selected from the group consisting of a tumor antigen, a microbial antigen, and an allergen.  
     
     
         24 . The method of  claim 23 , wherein the antigen is a tumor antigen.  
     
     
         25 . The method of  claim 21 , wherein the antigen is administered to the subject in conjunction with the immunostimulatory CpG oligonucleotide and the Flt3 ligand.  
     
     
         26 . The method of  claim 21 , wherein the subject is passively exposed to the antigen.  
     
     
         27 . The method of  claim 21 , wherein the subject has a neoplastic disorder.  
     
     
         28 . The method of  claim 21 , wherein the subject has a viral infection.  
     
     
         29 . The method of  claim 21 , wherein the subject is a non-human animal.  
     
     
         30 . The method of  claim 29 , wherein the non-human animal is a vertebrate animal selected from the group consisting of a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a chicken, and a primate.  
     
     
         31 . A composition, comprising: 
 an effective amount, for synergistically activating a dendritic cell, of an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:                                      5′ X 1 CGX 2  3′                                 wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X 1  and X 2  are nucleotides; and a Flt3 ligand.    
     
     
         32 . The composition of  claim 31 , further comprising an antigen and wherein the antigen and the CpG oligonucleotide are not conjugated.  
     
     
         33 . The composition of  claim 33 , wherein the antigen is selected from the group consisting of a cancer antigen, a microbial antigen, and an allergen.  
     
     
         34 . A method for activating a dendritic cell, comprising: 
 contacting a dendritic cell exposed to an antigen with an effective amount for synergistically activating a dendritic cell of a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:      5′X 1 CGX 2  3′   wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X 1  and X 2  are nucleotides, whereby an antigen is optionally additionally administered, and wherein the antigen and the CpG oligonucleotide are not conjugated.    
     
     
         35 . The method of  claim 34 , wherein the antigen is a tumor antigen.  
     
     
         36 . A method for treating a subject having a neoplastic disorder, comprising: 
 administering to the tumor of a subject having a neoplastic disorder a Flt3 ligand, and an immunostimulatory CpG oligonucleotide having a sequence including at least the following formula:                                      5′ X 1 CGX 2  3′                                 wherein the oligonucleotide is 8 to 100 nucleotides long, wherein C is unmethylated and wherein X 1  and X 2  are nucleotides, in an amount effective for synergistically increasing survival time of the subject with respect to a subject administered the immunostimulatory CpG oligonucleotide or the Flt3 ligand alone.    
     
     
         37 . The method of  claim 36 , wherein the tumor is selected from the group consisting of a lymphoma and a tumor of the brain, lung, ovary, breast, prostate, colon, and skin.  
     
     
         38 . The method of  claim 36 , wherein the immunostimulatory CpG oligonucleotide and the Flt3 ligand are injected directly into the tumor.  
     
     
         39 . The method of  claim 36 , wherein the subject is a non-human animal.  
     
     
         40 . The method of  claim 39 , wherein the non-human animal is a vertebrate animal selected from the group consisting of a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a chicken, and a primate.