Rig-i agonists and methods using same

Abstract

The present invention provides combination therapies that are useful for treating and/or preventing certain cancers. In certain embodiments, the therapy comprises an immune-checkpoint inhibitor and a RIG-I agonist. In other embodiments, the therapy comprises a RIG-I agonist.

What is claimed is: 
     
         1 . A method of treating a cancer; minimizing or preventing metastasis of a cancer; or inducing immune memory towards a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a RIG-I agonist. 
     
     
         2 . The method of  claim 1 , wherein the subject is further administered a therapeutically effective amount of an immune-checkpoint inhibitor, such as PD-1, PD-L1 or CTLA-4 blocking agents or antibodies. 
     
     
         3 . The method of  claim 2 , wherein the cancer is not significantly responsive to the immune-checkpoint inhibitor in the absence of the RIG-I inhibitor. 
     
     
         4 . The method of  claim 2 , wherein the immune-checkpoint inhibitor is at least one agent selected from the group consisting of PD-1/PD-L1 blockade agent and a CTLA-4 blocking agent. 
     
     
         5 . The method of  claim 4 , wherein the at least one agent is a small molecule drug, a polypeptide, and/or an antibody or a biologically active fragment thereof. 
     
     
         6 . The method of  claim 4 , wherein the at least one agent comprises at least one selected from the group consisting of durvalumab, atezolizumab, avelumab, nivolumab, AMP224 or GSK2661380, pidilizumab, pembrolizumab, BMS936559, RG7446, ipilimumab, and tremelimumab. 
     
     
         7 . The method of  claim 1 , wherein the RIG-1 agonist is a polyribonucleic acid (RNA) molecule capable of inducing an interferon response in the subject. 
     
     
         8 . The method of  claim 7 , wherein the RNA molecule is
 (i) a double stranded duplex or   (ii) a single chain molecule comprising a first nucleotide sequence, which 5′-end is conjugated to one end of an element selected from a loop and a linker, wherein the other end of the element is conjugated to the 3′-end of a second nucleotide sequence, wherein the first nucleotide sequence is substantially complementary to the second nucleotide sequence, wherein the first nucleotide sequence and the second nucleotide sequence can hybridize to form a double-stranded section, whereby the RNA molecule forms a hairpin structure;   wherein the number of base pairs in the double stranded section in (i) or (ii) is an integer ranging from 8 to 20.   
     
     
         9 . The method of  claim 8 , wherein the loop in (ii) comprises at least one nucleotide. 
     
     
         10 . The method of  claim 8 , wherein at least one of the following applies to the linker in (ii):
 (a) is free of a nucleoside, nucleotide, deoxynucleoside, or deoxynucleotide, or any surrogates or modifications thereof;   (b) is free of a phosphate backbone, or any surrogates or modifications thereof;   (c) comprises at least one selected from the group consisting of an ethylene glycol group, an amino acid, and an alkylene chain.   
     
     
         11 . The method of claim  10 (c), wherein the linker comprises (OCH 2 CH 2 ) n , wherein n is an integer ranging from 1 to 10. 
     
     
         12 . The method of  claim 8 , wherein the hairpin in (ii) has a blunt end. 
     
     
         13 . The method of  claim 8 , wherein the molecule has a 3′-overhang. 
     
     
         14 . The method of  claim 13 , wherein the overhang comprises one, two, or three non-base pairing nucleotides. 
     
     
         15 . The method of  claim 8 , wherein the RNA molecule comprises a 5′-terminus group selected from the group consisting of a 5′-triphosphate and a 5′-diphosphate. 
     
     
         16 . The method of  claim 8 , wherein the RNA molecule comprises a modified phosphodiester backbone. 
     
     
         17 . The method of  claim 8 , wherein the RNA molecule comprises at least one 2′-modified nucleotide. 
     
     
         18 . The method of  claim 17 , wherein the at least one 2′-modified nucleotide comprises a modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA). 
     
     
         19 . The method of  claim 8 , wherein the RNA molecule comprises at least one modified phosphate group, at least one modified base, or at least one abasic nucleotide. 
     
     
         20 . The method of  claim 8 , wherein the double-stranded section comprises one or more mispaired bases. 
     
     
         21 . The method of  claim 1 , wherein the cancer is immunogenic. 
     
     
         22 . The method of  claim 1 , wherein the cancer is not immunogenic. 
     
     
         23 . The method of  claim 1 , wherein the cancer is at least one selected from the group consisting of melanoma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, and lung cancer. 
     
     
         24 . The method of  claim 2 , wherein the immune-checkpoint inhibitor and the RIG-I agonist are co-administered or administered at approximately the same time to the subject. 
     
     
         25 . The method of  claim 1 , wherein the RIG-I agonist is administered intratumorally to the subject. 
     
     
         26 . The method of  claim 1 , wherein the RIG-1 agonist has abscopal effect in the subject. 
     
     
         27 . A pharmaceutical composition comprising an immune-checkpoint inhibitor and a RIG-I agonist. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the RIG-1 agonist is a RNA molecule capable of inducing an interferon response in a subject. 
     
     
         29 . The composition of  claim 28 , wherein the RNA molecule is a single chain molecule and comprises a first nucleotide sequence, which 5′-end is conjugated to one end of an element selected from a loop and a linker, wherein the other end of the element is conjugated to the 3′-end of a second nucleotide sequence, wherein the first nucleotide sequence is substantially complementary to the second nucleotide sequence, wherein the first nucleotide sequence and the second nucleotide sequence can hybridize to form a double-stranded section, wherein the number of base pairs in the double stranded section is an integer ranging from 8 to 20, whereby the RNA molecule forms a hairpin structure.