Method of Modulating the Number and the Distribution of Tumor-Infiltrating Leukocytes in Tumors

Abstract

The present invention is related to a molecule capable of inhibiting signaling between SDF-1 and CXCR4 and/or CXCR7, wherein the molecule is for use in a method of modulating the number and/or the spatial distribution of tumor-infiltrating leukocytes in a tumor and/or metastases.

1 .- 111 . (canceled) 
     
     
         112 . A method for establishing in the treatment and/or prevention of a tumor in a subject an SDF-1 gradient (a) in and/or around the tumor, (b) in and/or around metastases, (c) around the vasculature of the tumor and/or (d) around the vasculature of metastases, wherein the method comprises administering to the subject a molecule that inhibits signaling between SDF-1 and CXCR4 and/or CXCR7, wherein said molecule comprises an SDF-1 binding L-nucleic acid molecule. 
     
     
         113 . The method of  claim 112 , wherein the SDF-1 binding L-nucleic acid molecule is selected from the group consisting of an SDF-1 binding nucleic acid molecule of type B, an SDF-1 binding nucleic acid molecule of type C, an SDF-1 binding nucleic acid molecule of type A and an SDF-1 binding nucleic acid molecule of type D, wherein
 the SDF-1 binding nucleic acid molecule of type B comprises in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 52) 
                 
                 
                 
                 
               
                     
                     
                   5′ GUGUGAUCUAGAUGUADWGGCUGWUCCUAGUYAGG 3′; 
                 
             
                
               
            
             
                
               
            
           
         
         the SDF-binding nucleic acid molecule of type C comprises in 5′-3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 108) 
                 
                 
                 
                 
               
                     
                     
                   GGUYAGGGCUHRXAAGUCGG, 
                 
             
                
               
            
             
                
               
            
           
         
          wherein X A  is either absent or is A; 
         the SDF-binding nucleic acid molecule of type A comprises in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 74) 
                 
                 
                 
                 
               
                     
                     
                   5′ AAAGYRACAHGUMAAXAUGAAAGGUARC 3′, 
                 
             
                
               
            
             
                
               
            
           
         
          wherein X A  is either absent or is A; or 
         the SDF-1 binding nucleic acid molecule of type D comprises the nucleotide sequence according to any one of SEQ ID NO:142 to SEQ ID NO:144. 
       
     
     
         114 . The method of  claim 112 , wherein the method comprises modulating the number and/or the spatial distribution of tumor-infiltrating leukocytes in and/or around the tumor and/or metastases. 
     
     
         115 . The method of  claim 114 , wherein the modulation of the number and/or the spatial distribution results from the SDF-1 gradient. 
     
     
         116 . The method of  claim 112 , wherein the method comprises inducing leukocyte-mediated immune response against the tumor and/or the metastases. 
     
     
         117 . The method of  claim 116 , wherein leukocyte-mediated immune response comprises direct leukocyte-mediated cytotoxicity and leukocyte-mediated antibody-dependent cellular cytotoxicity. 
     
     
         118 . The method of  claim 117 , wherein leukocytes are NK cells, T cells or B cells. 
     
     
         119 . The method of  claim 112 , wherein the method comprises administering to the subject a therapeutically effective amount of the L-nucleic acid molecule. 
     
     
         120 . The method of  claim 112 , wherein the L-nucleic acid molecule
 a) increases the number of NK cells in the tumor and/or metastases, and/or   b) leads to a more homogeneous spatial distribution of NK cells in the tumor and/or metastases as compared to not using the method of  claim 112 , and/or   c) leads to a spatial distribution of NK cells to more compartments in the tumor and/or metastases as compared to not using the method of  claim 112 .   
     
     
         121 . The method of  claim 120 , wherein an NK cell immune response against the tumor and/or metastases is enhanced, and/or an NK cell antibody-dependent cellular cytotoxicity is enhanced. 
     
     
         122 . The method of  claim 121 , wherein the NK cell immune response against the tumor and/or metastases is enhanced, and/or the NK cell mediated antibody-dependent cellular cytotoxicity is enhanced which is achieved because of the effect of a), b) and/or c). 
     
     
         123 . The method of  claim 112 , wherein the L-nucleic acid molecule increases the number of T cells and/or B cells in the tumor and/or metastases. 
     
     
         124 . The method of  claim 123 , wherein the L-nucleic acid molecule increases the number of B cells in the tumor and/or metastases. 
     
     
         125 . The method of  claim 123 , wherein,
 a) the T cells are CD3 +  T cells, or   b) the T cells are cytotoxic T cells, or   c) the T cells are T helper cells.   
     
     
         126 . The method of  claim 112 , wherein the tumor is selected from the group consisting of a solid tumor, a lymphoma, a myeloma and precursor thereof. 
     
     
         127 . The method of  claim 113 , wherein the central stretch of nucleotides of a type B nucleic acid molecule comprises the following nucleotide sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 53) 
                 
                 
                 
                 
               
                     
                     
                   5′ GUGUGAUCUAGAUGUADUGGCUGAUCCUAGUCAGG 3′. 
                 
             
                
               
            
             
                
               
            
           
         
       
     
     
         128 . The method of  claim 113 , wherein the SDF-1 binding nucleic acid molecule of type B comprises the nucleotide sequence according to any one of SEQ ID NO:5 to SEQ ID NO:20 or SEQ ID NO:22 to SEQ ID NO:28. 
     
     
         129 . The method of  claim 128 , wherein the SDF-1 binding nucleic acid molecule of type B comprises the nucleotide sequence according to SEQ ID NO:22 or SEQ ID NO:28. 
     
     
         130 . The method of  claim 113 , wherein the central stretch of nucleotides of a type C SDF-1 binding nucleic acid molecule comprises the nucleotide sequence of 5′ GGUYAGGHRAAGUCGG 3′ (SEQ ID NO:109), 5′ GGUYAGGGCUHRAGUCGG 3′ (SEQ ID NO:110) or 5′ GGUUAGGGCUHGAAGUCGG 3′ (SEQ ID NO:111). 
     
     
         131 . The method of  claim 113 , wherein the type C SDF-1 binding nucleic acid molecule comprises the nucleotide sequence according to SEQ ID NO:95 to SEQ ID NO:107, SEQ ID NO:112 to SEQ ID NO:137, SEQ ID NO:223 or SEQ ID NO:224. 
     
     
         132 . The method of  claim 113 , wherein the central stretch of nucleotides of a type A SDF-1 binding nucleic acid molecule comprises the nucleotide sequence of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 75) 
                 
                 
                 
                 
               
                     
                     
                   5′ AAAGYRACAHGUMAAUGAAAGGUARC 3′, 
                 
                     
                     
                   or 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO: 76) 
                 
                 
                 
                 
               
                     
                     
                   5′ AAAGYRACAHGUMAAAUGAAAGGUARC 3′, 
                 
                     
                     
                   or 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO: 77) 
                 
                 
                 
                 
               
                     
                     
                   5′ AAAGYAACAHGUCAAUGAAAGGUARC 3′. 
                 
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         133 . The method of  claim 113 , wherein the SDF-1 binding nucleic acid molecule of type A comprises the nucleotide sequence according to SEQ ID NO:60 to SEQ ID NO:73, SEQ ID NO:78 to SEQ ID NO:82, SEQ ID NO:84 to SEQ ID NO:87, SEQ ID NO:89 to SEQ ID NO:94, SEQ ID NO:145 or SEQ ID NO:146. 
     
     
         134 . The method of  claim 112 , wherein the molecule comprises a modification that modifies residence time of the L-nucleic acid molecule in an animal or a human body. 
     
     
         135 . The method of  claim 134 , wherein the modification is selected from the group consisting of an HES moiety, a PEG moiety, biodegradable modifications thereof and combinations thereof.