Methods and Compositions for Treating Melanoma

Abstract

Compositions and methods for treating melanoma are provided. Compositions include BRAFV600E-based peptides, alone or admixed with T helper peptides. Other compositions include nucleic acid sequences encoding the BRAFV600E-based peptides, alone or admixed with nucleic acid sequences T helper peptides. Dendritic cells pretreated with the BRAFV600E-based peptides, alone or admixed with T helper peptides, are also provided. These compositions are useful to treat melanoma, optionally co-administered with antibodies to checkpoint inhibitors or molecules that mimic the action of such antibodies.

What is claimed is: 
     
         1 . A composition comprising a nucleic acid sequence encoding:
 (a) Xaa1-Xaa2-Leu-Xaa4-Thr-Glu-Lys-Ser-Arg-Trp-Ser-Xaa12-Xaa13-Xaa14 (SEQ ID NO: 4), wherein Xaa1, Xaa2, Xaa13, and Xaa14, are each independently absent, Ser, Gly, or Cys for coupling to an additional peptide or protein, and wherein amino acid Xaa4 is a substituted or unsubstituted Ile and amino acid Xaa12 is a hydrophobic amino acid; or   (b) Xaa1-Xaa2-Leu-Xaa4-Thr-Glu-Lys-Ser-Arg-Trp-Ser-Xaa12-Xaa13-Xaa14 (SEQ ID NO: 5), wherein Xaa1, Xaa2, Xaa13, and Xaa14 are each independently absent, Ser, Gly, or Cys for coupling to an additional peptide or protein, and wherein Xaa4 is a hydrophobic amino acid and Xaa12 is a substituted or unsubstituted Gly, Val or Leu;   (c) Xaa1-Xaa2-Leu-Xaa4-Thr-Glu-Lys-Ser-Arg-Trp-Ser-Xaa12-Xaa13-Xaa14 (SEQ ID NO: 6), wherein Xaa1, Xaa2, Xaa13, and Xaa14, are each independently absent, Ser, Gly, or Cys for coupling to an additional peptide or protein, and wherein Xaa4 is a substituted or unsubstituted Ile, Ala, Met or Leu, and wherein Xaa12 is a substituted or unsubstituted Gly, Ile, Val or Leu.   (d) a peptide or polypeptide encoding a fusion peptide comprising the peptide of (a), (b) or (c) fused to a T cell peptide at either the N- or C-termini; or   (e) a peptide or polypeptide encoding a fusion peptide comprising at least two copies of the same peptide of (a), (b), (c) or (d).   
     
     
         2 . The composition according to  claim 1 , further comprising a pharmaceutically acceptable vehicle or carrier. 
     
     
         3 . The composition according to  claim 1 , wherein said encoded peptide (a) or (b) is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 7) 
                 
                     
                   Xaa1-Xaa2-Leu-Ile-Thr-Glu-Lys- 
                 
                     
                     
                 
                     
                   Ser-Arg-Trp-Ser-Gly-Xaa13-Xaa14; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   Xaa1-Xaa2-Leu-Ile-Thr-Glu-Lys-Ser- 
                 
                     
                     
                 
                     
                   Arg-Trp-Ser-Val-Xaa13-Xaa14; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   Xaa1-Xaa2-Leu-Leu-Thr-Glu-Lys-Ser- 
                 
                     
                     
                 
                     
                   Arg-Trp-Ser-Val-Xaa13-Xaa14; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   Xaa1-Xaa2-Leu-Ala-Thr-Glu-Lys-Ser- 
                 
                     
                     
                 
                     
                   Arg-Trp-Ser-Ile-Xaa13-Xaa14; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                   Xaa1-Xaa2-Leu-Met-Thr-Glu-Lys-Ser- 
                 
                     
                     
                 
                     
                   Arg-Trp-Ser-Gly-Xaa13-Xaa14; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                   Xaa1-Xaa2-Leu-Ala-Thr-Glu-Lys-Ser- 
                 
                     
                     
                 
                     
                   Arg-Trp-Ser-Val-Xaa13-Xaa14. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The composition according to  claim 1 , further comprising an antibody that binds a checkpoint inhibitor or a molecule that mimics the function of a checkpoint inhibitor. 
     
     
         5 . The composition according to claim  27 , wherein the checkpoint inhibitor is CTLA4, PD1, PDL1, LAG3, ICOS, BTLA, KIR, OX40, CD27, CD40L, CD40, TIM3 or TIM334. 
     
     
         6 . A composition comprising a recombinant dendritic cell pretreated ex vivo with a composition of  claim 1 . 
     
     
         7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and at least one of
 (a) a BRAF V600E -based modified peptide or a pharmaceutically acceptable salt thereof,   (b) the composition of  claim 1 ,   (c) a nucleic acid sequence encoding (a) or (b), or   (d) a dendritic cell pretreated with (a), (b) or (c); and at least one of   (e) a T helper peptide,   (f) an antibody that binds a checkpoint inhibitor, or   (g) a synthetic small molecule that mimics the function of a checkpoint inhibitor.   
     
     
         8 . A method of treating or retarding or preventing the development of melanoma in a mammalian subject comprising administering to a subject in need thereof
 (a) a BRAF v600E -based modified peptide or a pharmaceutically acceptable salt thereof,   (b) a composition of  claim 1 ,   (c) a nucleic acid sequence encoding (a) or (b), or   (d) a dendritic cell pretreated with (a), (b) or (c).   
     
     
         9 . The method according to  claim 8 , further comprising administering to said subject at least one of
 (e) a T helper peptide, or a nucleic acid sequence encoding said peptide,   (f) an antibody that binds a checkpoint inhibitor, or   (g) a synthetic small molecule that mimics the function of a checkpoint inhibitor.