Method of eliciting an anti-tumor immune response with controlled delivery of TLR agonists in porous polymerlc devices

• US 10,568,949 B2
• Filed: 11/20/2017
• Issued: 02/25/2020
• Est. Priority Date: 02/13/2008
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Ali, Omar Abdel-Rahman, Dranoff, Glenn, Mooney, David J.
• Primary Examiner(s): Stoica, Elly-Gerald
• Application Number:
  US15/818,509
• Publication Number:
  US 20180289789A1
• Time in Patent Office: 827 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/55588 Adjuvants of undefined constitution
• CPC Class Codes: A61K 2039/6093 Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants

Abstract

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.

Claims

1. A device comprising a porous polymeric structure composition, and a toll-like receptor 3 (TLR3) agonist, wherein said TLR3 is in an amount effective to activate an antigen presenting cell.

2. The device of claim 1, further comprising a tumor antigen.

3. The device of claim 1, wherein said polymeric structure composition comprises poly-lactide-co-glycolide (PLG).

4. The device of claim 1, wherein said TLR3 agonist comprises polyinosine-polycytidylic acid (poly I:

C) or PEI- poly (I;

C).

5. The device of claim 1, further comprising pathogen associated molecular patterns (PAMPs).

6. The device of claim 1, wherein said TLR3 agonist comprises a nucleic acid.

7. The device of claim 1, further comprising a TLR9 agonist.

8. The device of claim 7, wherein said TLR9 agonist comprises a cytosine-guanosine oligonucleotide (CpG-ODN) or a PEI-CpG-ODN.

9. The device of claim 1, wherein said device further comprises a cytokine capable of recruiting an antigen presenting cell into the porous polymeric structure composition.

10. The device of claim 9, wherein said cytokine comprises granulocyte macrophage colony stimulating factor (GM-CSF), Flt3L, or CCL20.

11. The device of claim 9, wherein said cytokine comprises encapsulated GM-CSF.

12. The device of claim 2, wherein said tumor antigen comprises a tumor lysate, purified protein tumor antigen, or synthesized tumor antigen.

13. The device of claim 5, wherein said PAMPs comprises a monophosphoryl lipid A (MPLA).

14. The device of claim 7, wherein said TLR3 agonist comprises poly (I:

C) and said TLR9 agonist comprises CpG-ODN.

15. The device of claim 1, further comprising a TLR4 agonist.

16. The device of claim 15, wherein said TLR3 agonist comprises poly (I:

C) and said TLR4 agonist comprises MPLA.

17. The device of claim 1, wherein said TLR3 agonist is present in an amount to preferentially stimulate CD8+ dendritic cells or CD141+ dendritic cells.

26. The device of claim 1, wherein said antigen presenting cell is a dendritic cell.

18. A device comprising a polymeric structure composition, a toll-like receptor 3 (TLR3) agonist, and a second toll-like receptor (TLR) agonist selected from the group consisting of TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

19. A method for eliciting an anti-tumor immune response, comprising contacting or implanting into a subject a device comprising a polymeric structure composition, and a toll-like receptor 3 (TLR3) agonist, wherein said TLR3 agonist is in an amount effective to activate an antigen presenting cell.

20. The method of claim 19, wherein said device further comprises a tumor antigen.

21. The method of claim 19, wherein said device further comprises a TLR9 agonist.

22. The method of claim 19, wherein said anti-tumor immune response comprises activation of a CD8+ dendritic cell or a CD141+ dendritic cell.

23. The method of claim 21, wherein said anti-tumor immune response comprises activation of a plasmacytoid dendritic cell or a CD141+ dendritic cell.

24. The method of claim 20, wherein said anti-tumor immune response comprises a reduction in tumor burden.

25. The method of claim 19, wherein said TLR3 agonist is present at a concentration effective to induce production of interleukin-12 (IL-12) by dendritic cells.

27. The method of claim 19, wherein said antigen presenting cell is a dendritic cell.