Controlled delivery of TLR agonists in structural polymeric devices
The present invention comprises compositions, methods, and devices for creating an stimulating an antigen-specific dendritic cell immune response. Devices and methods provide prophylactic and therapeutic immunity to subjects against cancer and infectious agents.
1. A method for eliciting an anti-tumor immune response, comprising contacting or implanting into a subject a device comprising a polymeric structure composition, a tumor antigen, and a TLR3 agonist, wherein the TLR3 agonist comprises condensed polyinosine-polycytidylic acid (poly I:C) cationic nanoparticles, wherein said anti-tumor immune response comprises activation of a CD8+ dendritic cell, a plasmacytoid dendritic cell, or a CD141+ dendritic cell, and wherein said tumor comprises a solid tumor, said condensed poly I:C cationic nanoparticles being formed by mixing said poly I:C with a polycation comprising positively charged amine groups at a charge ratio resulting in positively charged condensates and an average particle size of 98-545 nm.
2. A method for eliciting an anti-tumor immune response, comprising contacting or implanting into a subject a device comprising a polymeric structure composition, a tumor antigen, a TLR3 agonist and a TLR9 agonist, wherein said anti-tumor immune response comprises activation of a CD8+ dendritic cell, a plasmacytoid dendritic cell, or a CD141+ dendritic cell, wherein said TLR3 agonist comprises condensed poly I:C cationic nanoparticles, and wherein said tumor comprises a solid tumor, said condensed poly I:C cationic nanoparticles being formed by mixing said poly I:C with a polycation comprising positively charged amine groups at a charge ratio resulting in positively charged condensates and an average particle size of 98-545 nm.
3. The method of claim 1 or 2 , wherein said anti-tumor immune response comprises a reduction in tumor burden.
4. The method of claim 1 , wherein said TLR3 agonist is present at a concentration effective to induce production of interleukin-12 (IL-12) by dendritic cells.
5. The method of claim 4 , wherein the device is implanted in the subject, and wherein 200-400 ng/mL of IL-12 is produced at the site of implantation.
6. The method of any of the claim 1 or 2 , wherein the condensed poly (I:C) cationic nanoparticle comprises PEI-poly(I:C).
7. The method of claim 2 , wherein the TLR9 agonist comprises a cytosine-guanosine oligonucleotide (CpG-ODN) or condensed CpG-ODN.
8. The method of claim 1 , wherein the polymeric structure composition comprises poly-lactide-co-glycolide (PLG).
9. The method of claim 1 , wherein the device further comprises pathogen associated molecular patterns (PAMPs).
10. The method of claim 2 , wherein the TLR3 or TLR9 agonist comprises a nucleic acid.
11. The method of claim 1 , wherein the device further comprises a recruitment composition.
12. The method of claim 11 , wherein the recruitment composition comprises granulocyte macrophage colony stimulating factor (GM-CSF), Flt3L, or CCL20.
13. The method of claim 12 , wherein the device comprises 0.5 μg to 500 μg of GM-CSF.
14. The method of claim 11 , wherein the recruitment composition comprises encapsulated GM-CSF.
15. The method of claim 1 , wherein the tumor antigen comprises a tumor lysate, purified protein tumor antigen, or synthesized tumor antigen.
16. The method of claim 1 , wherein the device comprises 100 μg-10,000 μg of tumor antigen.
17. The method of claim 1 , wherein the device is implanted at or near a tumor site in the subject, or at or near a site from which a tumor was removed from the subject.
18. The method of claim 1 , wherein the anti-tumor immune response is effective in treating a lung cancer.
19. The method of claim 1 , wherein the anti-tumor immune response is effective in treating a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcionoma, prostate cancer, Kaposi's sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.
20. The method of claim 1 , wherein the tumor antigen comprises an antigen from a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Leukemia, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcinoma, prostate cancer, Kaposi's sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.
21. The method of claim 2 , wherein the anti-tumor immune response is effective in treating a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Leukemia, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcinoma, prostate cancer, Kaposi's sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.
22. The method of claim 2 , wherein the tumor antigen comprises an antigen from a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Leukemia, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcinoma, prostate cancer, Kaposi's sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.
23. The method of claim 2 , wherein the device further comprises a recruitment composition.
24. The method of claim 23 , wherein the recruitment composition comprises granulocyte macrophage colony stimulating factor (GM-CSF), Flt3L, or CCL20.
25. The method of claim 2 , wherein the tumor antigen comprises a tumor lysate, purified protein tumor antigen, or synthesized tumor antigen.
26. The method of claim 1 , wherein the subject comprises a melanoma.
27. The method of claim 1 , wherein the subject comprises a lung cancer.
28. The method of claim 1 , wherein the subject comprises a central nervous system (CNS) cancer.
29. The method of claim 28 , wherein the device is implanted into the subject at or near a tumor site in the subject or at or near a site from which a tumor was removed from the subject.
30. The method of claim 28 , wherein the CNS cancer comprises a glioma.
31. The method of claim 1 or 2 , wherein said polymeric structure composition is anionic and said condensed poly I:C cationic nanoparticles are electrostatically immobilized on said anionic polymeric structure composition of said device.
32. The method of claim 1 , wherein said charge ratio comprises an amino-phosphate charge ratio of 3, 4, 7, or 15.
33. The method of claim 2 , wherein said charge ratio comprises an amino-phosphate charge ratio of 3, 4, 7, or 15.