COMPOSITIONS AND METHODS FOR ACTIVATING "STIMULATOR OF INTERFERON GENE"-DEPENDENT SIGNALLING
The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2′,5′,2′,5′ and 2′,5′,3′,5′ CDNs, and prefereably Rp,Rp stereosiomers thereof.
1 . A method of treating cancer in a subject in need thereof, comprising:
administering to the subject one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist; and
co-administering to the subject a cyclic dinucleotide that induces Stimulator of Interferon Genes (“STING”)-dependent type I interferon production.
2 . The method of claim 1 , wherein the cyclic dinucleotide has the formula:
where R 1 and R 2 are each H,
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered as separate administrations.
4 . The method of claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered at different times.
5 . The method of claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered by different routes of administration.
6 . The method of claim 1 , wherein the cancer is selected from the group consisting of a colorectal cancer, an aero-digestive squamous cancer, a lung cancer, a brain cancer, a liver cancer, a stomach cancer, a sarcoma, a leukemia, a lymphoma, a multiple myeloma, an ovarian cancer, a uterine cancer, a breast cancer, a melanoma, a prostate cancer, a pancreatic carcinoma, and a renal carcinoma.