Methods of modulating immune activity

Abstract

In one aspect, the invention provides methods of increasing immune response by administering postcellular signaling factors produced by cells exposed to a stress condition. In one aspect, the invention provides methods of increasing immune response by administering in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a purinergic receptor agonist. The increase in immune response may be used, for example, for treatment of infection or cancer. The invention also provides screening assays for identification of compounds that induce production of postcellular signaling factors which are also immunostimulatory agents. The invention further provides methods for identifying postcellular signaling factors with immunostimulatory activity. In another aspect, the invention provides methods of decreasing immune response by administering to a cell, tissue or subject a purinergic receptor antagonist alone or in combination with a Stimulator of Interferon Genes (STING) antagonist.

1 . A method of increasing immune activity in a target cell, tissue or subject, the method comprising administering to the target cell, tissue or subject, in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a P2Y2 receptor agonist, wherein the STING agonist and the P2Y2 receptor agonist are administered in an amount sufficient to increase the immune activity relative to a cell, tissue or subject that is not treated with the STING agonist and/or the P2Y2 receptor agonist. 
     
     
         2 . A method of increasing the level or activity of RF or STING in a target cell, tissue or subject, comprising administering to the target cell, tissue or subject, in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a P2Y2 receptor agonist, wherein the STING agonist and the P2Y2 receptor agonist are administered in an amount sufficient to increase the level or activity of RF or STING relative to a cell, tissue or subject that is not treated with the STING agonist and/or the P2Y2 receptor agonist. 
     
     
         3 . A method of treating a subject in need of increased immune activity, the method comprising administering to the subject, in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a P2Y2 receptor agonist, wherein the STING agonist and the P2Y2 receptor agonist are administered in an amount sufficient to increase the immune activity in the subject relative to a subject that is not treated with the STING agonist and/or the P2Y2 receptor agonist. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The method of  claim 3 , wherein the subject has a chronic infection. 
     
     
         8 . The method of  claim 7 , wherein the chronic infection is selected from HIV infection, HCV infection, HBV infection, HPV infection, Hepatitis B infection, Hepatitis C infection, EBV infection, CMV infection, TB infection, and infection with a parasite. 
     
     
         9 . A method of treating a subject diagnosed with cancer, comprising administering to the subject, in combination (a) a Stimulator of Interferon Genes (STING) agonist and (b) a P2Y2 receptor agonist, thereby treating the cancer in the subject. 
     
     
         10 . The method of  claim 9 , wherein the STING agonist and the P2Y2 receptor agonist act synergistically. 
     
     
         11 . The method of  claim 9 , wherein a response of the cancer to treatment is improved relative to a treatment with the STING agonist alone or the P2Y2 receptor agonist alone. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the response comprises any one or more of reduction in tumor burden, reduction in tumor size, inhibition of tumor growth, achievement of stable cancer in a subject with a progressive cancer prior to treatment, increased time to progression of the cancer, and increased time of survival. 
     
     
         14 . The method of  claim 9 , wherein the cancer is a cancer responsive to an immune checkpoint therapy. 
     
     
         15 . The method of  claim 9 , wherein the cancer is selected from a carcinoma, sarcoma, lymphoma, melanoma, and leukemia. 
     
     
         16 . The method of  claim 9 , wherein:
 (a) the STING agonist is a cyclic dinucleotide, optionally wherein the cyclic dinucleotide is selected from the group consisting of cGAMP, 2′3′-cGAMP, 3′3′-cGAMP, 3′3′-cGAMP-F, c-di-GMP, c-di-GMP-F, Rp/Sp, MK-1454, ADU-S100, and Disodium dithio-(RP, RP)-[cyclic [A(2′,5′)pA(3′,5′)p]] [Rp,Rp]-Cyclic(adenosine-(2′,5′) monophosphorothioateadenosine-(3′,5′)-monophosphorothioate) (disodium ADU-S100);   (b) the STING agonist is a flavonoid, optionally wherein the flavonoid is selected from the group consisting of 10-(carboxymethyl)-9(10H)acridone (CMA), 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or vadimezan, methoxyvone, 6, 4′-dimethoxyflavone, 4′-methoxyflavone, 3′, 6′-dihydroxyflavone, 7, 2′-dihydroxyflavone, daidzein, formononetin, retusin 7-methyl ether, xanthone, or any combination thereof;   (c) the STING agonist is an amidobenzimidazole compound or a dimeric amidobenzimidizole compound;   (d) the STING agonist is DNA; or   (e) the STING agonist is a type I interferon (IFN), optionally wherein the type I IFN is interferon-β or interferon-α.   
     
     
         17 - 23 . (canceled) 
     
     
         24 . The method of  claim 9 , wherein the P2Y2 receptor agonist is a small molecule. 
     
     
         25 - 30 . (canceled) 
     
     
         31 . The method of  9 , wherein the P2Y2, receptor agonist is a compound selected from the following: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 - 35 . (canceled) 
     
     
         36 . The method of  claim 9 , wherein the subject is human. 
     
     
         37 . The method of  claim 1 , wherein the STING agonist and the P2Y2 receptor agonist are administered in an amount sufficient to increase in the cell, tissue or subject one or more of: the level or activity of type I interferon, the level or activity of TBK1, the level or activity of IRF, the level or activity of NFkB, the level or activity of macrophages, the level or activity of monocytes, the level or activity of dendritic cells, the level or activity of T cells, the level or activity of CD4+, CD8+ or CD3+ cells, and the level or activity of a pro-immune cytokine. 
     
     
         38 . The method of  claim 9 , further comprising administering an immunotherapeutic to the subject. 
     
     
         39 . The method of  claim 38 , wherein the immunotherapeutic is selected from the group consisting of a Toll-like receptor (TLR) agonist, a cell-based therapy, a cytokine, a cancer vaccine, and an immune checkpoint modulator of an immune checkpoint molecule. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 39 , wherein the immune checkpoint molecule is selected from CD27, CD28, CD40, CD122, OX40, GITR, ICOS, 4-1BB, ADORA2A, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, and VISTA. 
     
     
         42 - 43 . (canceled) 
     
     
         44 . The method of  claim 39 , wherein the immune checkpoint modulator is selected from a small molecule, an inhibitory RNA, an antisense molecule, and an immune checkpoint molecule binding protein. 
     
     
         45 . The method of  claim 39 , wherein:
 a) the immune checkpoint molecule is PD-1 and the immune checkpoint modulator is a PD-1 inhibitor, optionally wherein the PD-1 inhibitor is selected from pembrolizumab, nivolumab, pidilizumab, SHR-1210, MEDI0680R01, BBg-A317, TSR-042, REGN2810 and PF-06801591;   b) the immune checkpoint molecule is PD-L1 and the immune checkpoint modulator is a PD-L1 inhibitor, optionally wherein the PD-L1 inhibitor is selected from durvalumab, atezolizumab, avelumab, MDX-1105, AMP-224 and LY3300054; or   c) the immune checkpoint molecule is CTLA-4 and the immune checkpoint modulator is a CTLA-4 inhibitor, optionally wherein the CTLA-4 inhibitor is selected from ipilimumab, tremelimumab, JMW-3B3 and AGEN1884.   
     
     
         46 - 198 . (canceled)