VIP Antagonists and Uses in Treating Cancer

Abstract

This disclosure relates to methods of treating cancer or viral infections comprising administering an effective amount of a VIP antagonist in combination with an immune check-point inhibitor to a subject in need thereof. In certain embodiments, the immune check-point inhibitor is an anti-PD1 or anti-PDL1 antibody.

1 . A method of treating a cancer in a subject comprising
 obtaining a T cell;   exposing the T cell in vitro or ex vivo to a vasoactive intestinal polypeptide (VIP) antagonist and an immune check-point inhibitor thereby expanding the T cell; and   administering an effective amount of the expanded T cell to the subject.   
     
     
         2 . The method of  claim 1 , further comprising exposing the T cell in vitro or ex vivo to an anti-CD3 antibody, an anti-CD28 antibody, and/or a tumor antigen. 
     
     
         3 . The method of  claim 1 , wherein the T cell is obtained from the subject. 
     
     
         4 . The method of  claim 1 , wherein T cell is a senescent T cell prior to the in vitro or ex vivo exposure. 
     
     
         5 . The method of  claim 1 , wherein the T cell is activated after the in vitro or ex vivo exposure. 
     
     
         6 . The method of  claim 1 , further comprising administering to the subject an effective amount of a VIP antagonist. 
     
     
         7 . The method of  claim 1 , further comprising administering to the subject an effective amount of an immune check-point inhibitor. 
     
     
         8 . The method of  claim 7 , wherein the immune check-point inhibitor is an anti-PD1 antibody or an anti-PDL1 antibody. 
     
     
         9 . The method of  claim 8 , wherein the anti-PD1 antibody is pembrolizumab or nivolumab. 
     
     
         10 . The method of  claim 8 , wherein the anti-PDL1 antibody is atezolizumab, avelumab, or durvalumab. 
     
     
         11 . The method of  claim 7 , wherein the immune check-point inhibitor is ipilimumab. 
     
     
         12 . The method of  claim 1 , wherein the vasoactive intestinal polypeptide antagonist is composed of the sequence (SEQ ID NO: 1) KPRRPYTDNYTRLRKQMAVKKYLNSILN. 
     
     
         13 . The method of  claim 1 , wherein the VIP antagonist is selected from the group consisting of
 [Ac-Tyr1,D-Phe2]GRF 1-29, amide, i.e., (SEQ ID NO: 4)
 YFDAIFTNSYRKVLGQLSARKLLQDIMSR (Modifications: Tyr-1=N-terminal Ac, Phe-2=D-Phe, Arg-29=C-terminal amide); 
   VIP (6-28), i.e., (SEQ ID NO:5) FTDNYTRLRKQMAVKKYLNSILN (Modifications: Asn-23=C-terminal amide);   [D-p-Cl-Phe6, Leu17]-VIP, i.e., (SEQ ID NO: 6)
 HSDAVFTDNYTRLRKQLAVKKYLNSILN (Modifications: Phe-6=p-Cl-D-Phe, Asn=C-terminal amide); 
   N-terminal Stearyl, Norleucine 17 VIPhyb, i.e., (SEQ ID NO: 9)
 KPRRPYTDNYTRLRKQXAVKKYLNSILN, wherein X is norleucine; 
   Ac His1 [D-Phe(2), Lys(15), Arg(16), Leu(27)]-VIP(1-7)/GRF(8-27), i.e., (SEQ ID NO:10) HFDAVFTNSYRKVLKRLSARKLLQDIL, C-terminal amide; and   pituitary adenylate cyclase-activating polypeptide, PACAP (6-38) C-terminal amide, i.e., (SEQ ID NO:11) TDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK.   
     
     
         14 . The method of  claim 1 , wherein the VIP antagonist is conjugated with a nanoparticle. 
     
     
         15 . A method of enhancing an immune response to a cancer in a subject or treating a cancer in a subject, the method comprising administering to the subject an effective amount of a vasoactive intestinal peptide signalling (VIP) antagonist, an immune check-point inhibitor, and an anti-cancer antibody to a subject in need thereof. 
     
     
         16 . The method of  claim 15 , wherein the immune check-point inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody. 
     
     
         17 . The method of  claim 16 , wherein the anti-PD1 antibody is pembrolizumab or nivolumab. 
     
     
         18 . The method of  claim 16 , wherein the anti-PDL1 antibody is atezolizumab, avelumab, or durvalumab. 
     
     
         19 . The method of  claim 15 , wherein the immune check-point inhibitor is ipilimumab. 
     
     
         20 . The method of  claim 15 , wherein the anti-cancer antibody is selected from an anti-CD19 antibody, an anti-CD123 antibody, an anti-HER2/neu antibody, an anti-BMCA antibody, and an anti-EGFR antibody. 
     
     
         21 . The method of  claim 15 , wherein the VIP antagonist is composed of the sequence (SEQ ID NO: 1) KPRRPYTDNYTRLRKQMAVKKYLNSILN. 
     
     
         22 . The method of  claim 15 , wherein the VIP antagonist is selected from the group consisting of
 [Ac-Tyr1,D-Phe2]GRF 1-29, amide, i.e., (SEQ ID NO: 4)
 YFDAIFTNSYRKVLGQLSARKLLQDIMSR (Modifications: Tyr-1=N-terminal Ac, Phe-2=D-Phe, Arg-29=C-terminal amide); 
   VIP (6-28), i.e., (SEQ ID NO:5) FTDNYTRLRKQMAVKKYLNSILN (Modifications: Asn-23=C-terminal amide);
 [D-p-Cl-Phe6, Leu17]-VIP, i.e., (SEQ ID NO: 6) 
 HSDAVFTDNYTRLRKQLAVKKYLNSILN (Modifications: Phe-6=p-Cl-D-Phe, Asn=C-terminal amide); 
   N-terminal Stearyl, Norleucine 17 VIPhyb, i.e., (SEQ ID NO: 9)
 KPRRPYTDNYTRLRKQXAVKKYLNSILN, wherein X is norleucine; 
   Ac His1 [D-Phe(2), Lys(15), Arg(16), Leu(27)]-VIP(1-7)/GRF(8-27), i.e., (SEQ ID NO:10) HFDAVFTNSYRKVLKRLSARKLLQDIL, C-terminal amide; and   pituitary adenylate cyclase-activating polypeptide, PACAP (6-38) C-terminal amide, i.e., (SEQ ID NO:11) TDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK.   
     
     
         23 . The method of  claim 15 , wherein the VIP antagonist is conjugated to a nanoparticle.