Combination tumor immunotherapy

Abstract

Provided are methods for treating cancer using local administration of certain CpG oligonucleotides (CpG ODN) and systemic administration of a checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CLA-4 antibody. In preferred embodiments, the CpG ODN are selected based on their propensity to induce high amounts of interferon alpha (IFN-α) and T-cell activation relative to interleukin-10 (IL-10) and B-cell activation. In certain embodiments, the methods further include pretreatment with radiotherapy, to potentiate the combination immunotherapy.

I claim: 
     
         1 . A method of treating a cancerous tumor, comprising
 administering to a subject in need thereof an effective amount of a TLR9 agonist and a checkpoint inhibitor (CPI), wherein the TLR9 agonist is administered into or substantially adjacent to the tumor.   
     
     
         2 . The method of  claim 1 , wherein the TLR9 agonist induces IFN-α. 
     
     
         3 . The method of  claim 1  or  2 , wherein the TLR9 agonist is CpG DNA. 
     
     
         4 . The method of any one of the preceding claims, wherein the TLR9 agonist is selected from the group consisting of A-class CpG DNA, C-class CpG DNA, E-class CpG DNA, A/E-class CpG DNA, P-class CpG DNA, and any combination thereof. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the TLR9 agonist is an A-class CpG DNA. 
     
     
         6 . The method of  claim 5 , wherein the sequence of the A-class CpG DNA is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 82) 
                 
                     
                   GGGGGGGGGGGACGATCGTCGGGGGGGGGG. 
                 
             
                
                
               
            
           
         
       
     
     
         7 . The method of  claim 5  or  6 , wherein the A-class CpG DNA is formulated as a virus-like particle. 
     
     
         8 . The method of any one of  claims 1 - 4 , wherein the TLR9 agonist is a C-class CpG DNA. 
     
     
         9 . The method of any one of the preceding claims, wherein the CPI is administered systemically. 
     
     
         10 . The method of any one of the preceding claims, wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to an antigen selected from the group consisting of PD-1, PD-L1, and CTLA-4. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         12 . The method of any one of  claims 1 - 10 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         13 . The method of any one of  claims 1 - 10 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to CTLA-4. 
     
     
         14 . The method of any one of  claims 1 - 10 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to an antigen selected from the group consisting of PD-1 and PD-L1. 
     
     
         15 . The method of any one of  claims 1 - 10 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         16 . The method of any one of  claims 1 - 10 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         17 . The method of any one of  claims 1 - 10 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to PD-1, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         18 . The method of any one of the preceding claims, wherein the TLR9 agonist is administered prior to administration of the CPI. 
     
     
         19 . The method of any one of  claims 1 - 17 , wherein the TLR9 agonist and the CPI are administered substantially at the same time. 
     
     
         20 . The method of any one of the preceding claims, wherein the cancerous tumor is a lymphoma or a cancerous tumor of a tissue or organ selected from the group consisting of skin, head and neck, esophagus, stomach, liver, colon, rectum, pancreas, lung, breast, cervix, ovary, kidney, bladder, prostate, thyroid, brain, muscle, and bone. 
     
     
         21 . The method of any one of the preceding claims, wherein the cancerous tumor is melanoma. 
     
     
         22 . The method of  claim 20 , wherein the cancerous tumor is a lymphoma. 
     
     
         23 . The method of any one of the preceding claims, wherein the cancerous tumor is resistant to a treatment regimen comprising administration of the CPI without administration of the TLR9 agonist. 
     
     
         24 . The method of any one of the preceding claims, wherein the subject is a human. 
     
     
         25 . A method of treating a cancerous tumor, comprising
 administering to a subject in need thereof an effective amount of radiotherapy, a TLR9 agonist, and a checkpoint inhibitor (CPI), wherein the radiotherapy is initiated prior to administration of the TLR9 agonist, and the TLR9 agonist is administered into or substantially adjacent to the tumor.   
     
     
         26 . The method of  claim 25 , wherein the TLR9 agonist induces IFN-α. 
     
     
         27 . The method of  claim 25  or  26 , wherein the TLR9 agonist is CpG DNA. 
     
     
         28 . The method of any one of  claims 25 - 27 , wherein the TLR9 agonist is selected from the group consisting of A-class CpG DNA, C-class CpG DNA, E-class CpG DNA, A/E-class CpG DNA, P-class CpG DNA, and any combination thereof. 
     
     
         29 . The method of any one of  claims 25 - 27 , wherein the TLR9 agonist is an A-class CpG DNA. 
     
     
         30 . The method of  claim 29 , wherein the sequence of the A-class CpG DNA is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 82) 
                 
                     
                   GGGGGGGGGGGACGATCGTCGGGGGGGGGG. 
                 
             
                
                
               
            
           
         
       
     
     
         31 . The method of  claim 29  or  30 , wherein the A-class CpG DNA is formulated as a virus-like particle. 
     
     
         32 . The method of any one of  claims 25 - 27 , wherein the TLR9 agonist is a C-class CpG DNA. 
     
     
         33 . The method of any one of  claims 25 - 32 , wherein the CPI is administered systemically. 
     
     
         34 . The method of any one of  claims 25 - 33 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to an antigen selected from the group consisting of PD-1, PD-L1, and CTLA-4. 
     
     
         35 . The method of any one of  claims 25 - 34 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         36 . The method of any one of  claims 25 - 34 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         37 . The method of any one of  claims 25 - 34 , wherein the CPI is an antibody or antigen-binding fragment thereof which binds specifically to CTLA-4. 
     
     
         38 . The method of any one of  claims 25 - 34 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to an antigen selected from the group consisting of PD-1 and PD-L i. 
     
     
         39 . The method of any one of  claims 25 - 34 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         40 . The method of any one of  claims 25 - 34 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to CTLA-4, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         41 . The method of any one of  claims 25 - 34 , wherein the CPI comprises (i) a first antibody or antigen-binding fragment thereof which binds specifically to PD-1, and (ii) a second antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         42 . The method of any one of  claims 25 - 41 , wherein the TLR9 agonist is administered prior to administration of the CPI. 
     
     
         43 . The method of any one of  claims 25 - 41 , wherein the TLR9 agonist and the CPI are administered substantially at the same time. 
     
     
         44 . The method of any one of  claims 25 - 43 , wherein the cancerous tumor is a lymphoma or a cancerous tumor of a tissue or organ selected from the group consisting of skin, head and neck, esophagus, stomach, liver, colon, rectum, pancreas, lung, breast, cervix, ovary, kidney, bladder, prostate, thyroid, brain, muscle, and bone. 
     
     
         45 . The method of any one of  claims 25 - 44 , wherein the cancerous tumor is melanoma. 
     
     
         46 . The method of  claim 44 , wherein the cancerous tumor is a lymphoma. 
     
     
         47 . The method of any one of  claims 25 - 46 , wherein the cancerous tumor is resistant to a treatment regimen comprising administration of the CPI without administration of the TLR9 agonist. 
     
     
         48 . The method of any one of  claims 25 - 47 , wherein the subject is a human. 
     
     
         49 . A method of treating a cancerous tumor, comprising
 administering to a subject in need thereof an effective amount of a TLR9 agonist, a first checkpoint inhibitor (CPI), and a second CPI, wherein the TLR9 agonist and the first CPI are administered into or substantially adjacent to the tumor, and the second CPI is administered systemically.   
     
     
         50 . The method of  claim 49 , wherein the TLR9 agonist induces IFN-α. 
     
     
         51 . The method of  claim 49  or  50 , wherein the TLR9 agonist is CpG DNA. 
     
     
         52 . The method of any one of  claims 49 - 51 , wherein the TLR9 agonist is selected from the group consisting of A-class CpG DNA, C-class CpG DNA, E-class CpG DNA, A/E-class CpG DNA, P-class CpG DNA, and any combination thereof. 
     
     
         53 . The method of any one of  claims 49 - 51 , wherein the TLR9 agonist is an A-class CpG DNA. 
     
     
         54 . The method of  claim 53 , wherein the sequence of the A-class CpG DNA is 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 82) 
                 
                     
                   GGGGGGGGGGGACGATCGTCGGGGGGGGGG. 
                 
             
                
                
               
            
           
         
       
     
     
         55 . The method of  claim 53  or  54 , wherein the A-class CpG DNA is formulated as a virus-like particle. 
     
     
         56 . The method of any one of  claims 49 - 51 , wherein the TLR9 agonist is a C-class CpG DNA. 
     
     
         57 . The method of any one of  claims 49 - 56 , wherein the first CPI is an antibody or antigen-binding fragment thereof which binds specifically to CTLA-4. 
     
     
         58 . The method of any one of  claims 49 - 56 , wherein the first CPI is an antibody or antigen-binding fragment thereof which binds specifically to CTLA-4; and the second CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         59 . The method of any one of  claims 49 - 56 , wherein the first CPI is an antibody or antigen-binding fragment thereof which binds specifically to CTLA-4; and the second CPI is an antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         60 . The method of any one of  claims 49 - 56 , wherein the first CPI comprises a first antibody or antigen-binding fragment thereof which binds specifically to PD-1, and the second CPT comprises a second antibody or antigen-binding fragment thereof which binds specifically to PD-L1. 
     
     
         61 . The method of any one of  claims 49 - 56 , wherein the first CPI comprises a first antibody or antigen-binding fragment thereof which binds specifically to PD-L1, and the second CPI comprises a second antibody or antigen-binding fragment thereof which binds specifically to PD-1. 
     
     
         62 . The method of any one of  claims 49 - 61 , wherein the TLR9 agonist is administered prior to administration of the first CPI. 
     
     
         63 . The method of any one of  claims 49 - 61 , wherein the TLR9 agonist and the first CPI are administered substantially at the same time. 
     
     
         64 . The method of any one of  claims 49 - 61 , wherein the TLR9 agonist is administered after administration of the first CPI. 
     
     
         65 . The method of any one of  claims 49 - 64 , wherein the cancerous tumor is a lymphoma or a cancerous tumor of a tissue or organ selected from the group consisting of skin, head and neck, esophagus, stomach, liver, colon, rectum, pancreas, lung, breast, cervix, ovary, kidney, bladder, prostate, thyroid, brain, muscle, and bone. 
     
     
         66 . The method of any one of  claims 49 - 65 , wherein the cancerous tumor is melanoma. 
     
     
         67 . The method of  claim 65 , wherein the cancerous tumor is a lymphoma. 
     
     
         68 . The method of any one of  claims 49 - 67 , wherein the cancerous tumor is resistant to a treatment regimen comprising administration of the first CPI without administration of the TLR9 agonist. 
     
     
         69 . The method of any one of  claims 49 - 68 , wherein the subject is a human.