Combination Vaccine Devices and Methods of Killing Cancer Cells

• US 20170042995A1
• Filed: 04/30/2015
• Published: 02/16/2017
• Est. Priority Date: 04/30/2014
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Ali, Omar abdel-Rahman, Mooney, David J., Dranoff, Glenn
• Granted Patent: US 10,682,400 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/5152 Tumor cells
• 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 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/64 characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/001102 Receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: A61K 39/001156 Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]
• CPC Class Codes: A61K 39/001157 Telomerase or TERT [telomerase reverse transcriptase]
• CPC Class Codes: A61K 39/00117 Mucins, e.g. MUC-1
• CPC Class Codes: A61K 39/001171 Gangliosides, e.g. GM2, GD2 or GD3
• CPC Class Codes: A61K 39/00118 from embryonic or fetal origin
• CPC Class Codes: A61K 39/001182 Carcinoembryonic antigen [CEA]
• CPC Class Codes: A61K 39/001186 MAGE
• CPC Class Codes: A61K 39/001191 Melan-A/MART
• CPC Class Codes: A61K 39/001192 Glycoprotein 100 [Gp100]
• CPC Class Codes: A61K 39/02 Bacterial antigens
• CPC Class Codes: A61K 39/12 : Viral antigens
• CPC Class Codes: A61K 39/39 : characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/3955 : against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/34 : Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/36 : Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/3053 : Skin, nerves, brain
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention comprises compositions, methods, and devices for enhancing an endogenous immune response against a cancer. Devices and methods provide therapeutic immunity to subjects against cancer.

Claims

1. A device comprising:

a) an inhibitor of an immune-inhibitory protein;

b) a scaffold composition;

c) a cell recruitment composition; and

d) a bioactive composition, wherein the bioactive composition is incorporated into or coated onto the scaffold composition, and wherein the bioactive composition causes modification of cells in or recruited to the device.

2. The device of claim 1, wherein the immune-inhibitory protein is selected from the group consisting of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1), programmed cell death protein 1 ligand (PDL1), lymphocyte activation gene 3 (LAG3), B7-H3, B7-H4, and T cell membrane protein 3 (TIM3).

3. The device of claim 2, wherein the immune-inhibitory protein is CTLA4.

4. The device of claim 2, wherein the immune-inhibitory protein is PD1.

5. The device of claim 1, comprising an inhibitor of CTLA4 and an inhibitor of PD1.

6. The device of claim 1, wherein the inhibitor comprises a protein, peptide, or nucleic acid.

7. The device of claim 2, wherein the inhibitor comprises an antibody or fragment thereof.

8. The device of claim 7 wherein the antibody or fragment thereof binds to CTLA4.

9. The device of claim 8, wherein the antibody or fragment thereof is Ipilimumab, Tremelimumab, or a fragment thereof.

10. The device of claim 2, wherein the inhibitor binds to PD1, and wherein the inhibitor is a protein.

11. The device of claim 10, wherein the inhibitor is MDX-1106, MK3475, CT-011, AMP-224, or a fragment thereof.

12. The device of claim 10, wherein the inhibitor is a PDL2-immunoglobulin (Ig) fusion protein.

13. The device of claim 2, wherein the inhibitor is a protein, and wherein the inhibitor binds to PDL1.

14. The device of claim 13, wherein the inhibitor is MDX-1105.

15. The device of claim 2, wherein the inhibitor is a protein, and wherein the inhibitor binds to LAG3.

16. The device of claim 15, wherein the inhibitor is a LAG3-Ig fusion protein.

17. The device of claim 16, wherein the LAG3-Ig fusion protein is IMP321.

18. The device of claim 2, wherein the inhibitor is a protein, and wherein the inhibitor binds to B7-H3.

19. The device of claim 18, wherein the inhibitor is MGA271.

20. The device of claim 1, wherein the cell recruitment composition recruits an immune cell.

21. The device of claim 20, wherein the immune cell comprises an antigen presenting cell.

22. The device of claim 21, wherein the antigen presenting cell comprises a dendritic cell.

23. The device of claim 20, wherein the immune cell comprises a macrophage, a T cell, a B cell, a natural killer (NK) cell, or a dendritic cell.

24. The device of claim 1, wherein the scaffold comprises open, interconnected macropores.

25. The device of claim 1, further comprising a deployment signal capable of inducing or promoting migration of cells.

26. The device of claim 25, wherein the deployment signal comprises a protein, peptide, or nucleic acid.

27. The device of claim 25, wherein the deployment signal comprises

i) one or more factors that induces migration of cells and has or is capable of forming a gradient;

ii) a nucleic acid molecule encoding a protein that induces migration of cells out of the device;

or

iii) depletion or diffusion of the cell recruitment composition.

28. The device of claim 1, wherein the cell recruitment composition comprises a cytokine, chemokine, or growth factor.

29. The device of claim 1, wherein the cell recruitment composition comprises GM-CSF, Flt3L, or CCL20.

30. The device of claim 1, wherein the bioactive composition comprises a target antigen composition.

31. The device of claim 1, wherein the cell recruitment composition recruits an immune cell to the device, where the immune cells encounters the target antigen, and where the immune cell resides until a deployment signal induces egress of the immune cell to a lymph node tissue outside of the device.

32. The device of claim 31, wherein the level of immune activation of the immune cell at egress is greater than that prior to entering the device.

33. The device of claim 31, wherein the immune cell is antigen-primed at egress compared to the level of priming prior to entering the device.

34. The device of claim 30, wherein the target antigen composition comprises a cancer antigen or a cancer derived antigen.

35. The device of claim 1, wherein the cancer cell is derived from a melanoma, a central nervous system (CNS) cancer, a CNS germ cell tumor, a lung cancer, leukemia, multiple myeloma, a renal cancer, a malignant glioma, a medulloblatoma, a breast cancer, an ovarian cancer, a prostate cancer, a bladder cancer, a fibrosarcoma, a pancreatic cancer, a gastric cancer, a head and neck cancer, or a colorectal cancer.

36. The device of claim 34, wherein the cancer-derived antigen is selected from the group consisting of MAGE series of antigens, MART-1/melanA, Tyrosinase, ganglioside, gp100, GD-2, O-acetylated GD-3, GM-2, MUC-1, Sos1, Protein kinase C-binding protein, Reverse transcriptase protein, AKAP protein, VRK1, KIAA1735, T7-1, T11-3, T11-9, Homo Sapiens telomerase ferment (hTRT), Cytokeratin-19 (CYFRA21-1), SQUAMOUS CELL CARCINOMA ANTIGEN 1 (SCCA-1), (PROTEIN T4-A), SQUAMOUS CELL CARCINOMA ANTIGEN 2 (SCCA-2), Ovarian carcinoma antigen CA125 (1A1-3B) (KIAA0049), MUCIN 1 (TUMOR-ASSOCIATED MUCIN), (CARCINOMA-ASSOCIATED MUCIN), (POLYMORPHIC EPITHELIAL MUCIN), (PEM), (PEMT), (EPISIALIN), (TUMOR-ASSOCIATED EPITHELIAL MEMBRANE ANTIGEN), (EMA), (H23AG), (PEANUT-REACTIVE URINARY MUCIN), (PUM), (BREAST CARCINOMA-ASSOCIATED ANTIGEN DF3), CTCL tumor antigen se1-1, CTCL tumor antigen se14-3, CTCL tumor antigen se20-4, CTCL tumor antigen se20-9, CTCL tumor antigen se33-1, CTCL tumor antigen se37-2, CTCL tumor antigen se57-1, CTCL tumor antigen se89-1, Prostate-specific membrane antigen, 5T4 oncofetal trophoblast glycoprotein, Orf73 Kaposi'"'"'s sarcoma-associated herpesvirus, MAGE-C1 (cancer/testis antigen CT7), MAGE-B1 ANTIGEN (MAGE-XP ANTIGEN) (DAM10), MAGE-B2 ANTIGEN (DAM6), MAGE-2 ANTIGEN, MAGE-4a antigen, MAGE-4b antigen, Colon cancer antigen NY-CO-45, Lung cancer antigen NY-LU-12 variant A, Cancer associated surface antigen, Adenocarcinoma antigen ART1, Paraneoplastic associated brain-testis-cancer antigen (onconeuronal antigen MA2;

paraneoplastic neuronal antigen), Neuro-oncological ventral antigen 2 (NOVA2), Hepatocellular carcinoma antigen gene 520, TUMOR-ASSOCIATED ANTIGEN CO-029, Tumor-associated antigen MAGE-X2, Synovial sarcoma, X breakpoint 2, Squamous cell carcinoma antigen recognized by T cell, Serologically defined colon cancer antigen 1, Serologically defined breast cancer antigen NY-BR-15, Serologically defined breast cancer antigen NY-BR-16, Chromogranin A, parathyroid secretory protein 1, DUPAN-2, CA 19-9, CA 72-4, CA 195, and Carcinoembryonic antigen (CEA).

37. The device of claim 1, wherein the bioactive composition comprises a tumor lysate.

38. The device of claim 1, wherein the bioactive composition comprises irradiated tumor cells.

39. The device of claim 1, wherein the bioactive composition comprises a cancer cell surface antigen.

40. The device of claim 1, wherein the bioactive composition comprises a viral or bacterial antigen.

41. The device of claim 1, wherein the device further comprises an adjuvant.

42. The device of claim 41, wherein the adjuvant comprises a CpG rich oligonucleotide.

43. The device of claim 42, wherein the adjuvant comprises a condensed CpG oligonucleotide.

44. The device of claim 43, wherein the adjuvant comprises a PEI-CpG oligonucleotide.

45. The device of claim 1, wherein the scaffold further comprises an RGD-modified alginate.

46. The device of claim 1, wherein the device further comprises a toll-like receptor (TLR) agonist.

47. The device of claim 46, wherein the TLR agonist preferentially binds to TLR3.

48. The device of claim 46, wherein the TLR agonist comprises a TLR3 agonist.

49. The device of claim 48, wherein the TLR3 agonist comprises polyinosine-polycytidylic acid (poly I:

C) or PEI-poly (I;

C).

50. The device of claim 1, wherein the scaffold comprises a hydrogel or porous polymer, said scaffold comprising a polymer or co-polymer of polylactic acid, polyglycolic acid, PLGA, alginate, gelatin, collagen, agarose, poly(lysine), polyhydroxybutyrate, poly-epsilon-caprolactone, polyphosphazines, poly(vinyl alcohol), poly(alkylene oxide), poly(ethylene oxide), poly(allylamine), poly(acrylate), poly(4-aminomethylstyrene), pluronic polyol, polyoxamer, poly(uronic acid), poly(anhydride) or poly(vinylpyrrolidone).

51. The device of claim 50, wherein the porous polymer is produced by gas-foaming.

52. The device of claim 1, wherein the device is in the form of a bead, pellet, sheet, or disc.

53. A method of killing a cancer cell in a subject in need thereof comprising administering the device of claim 1.

65. The method of claim 53, wherein the device is implanted subcutaneously into the subject.

70. The method of claim 53, wherein the subject comprises a cancer cell, wherein the cancer cell is poorly immunogenic.

71. The method of claim 70, wherein the cancer cell is resistant to cytotoxic T-lymphocyte (CTL)-mediated lysis.

72. The method of claim 70, wherein the cancer cell is resistant to natural killer (NK) cell mediated killing.

73. The method of claim 53, wherein the subject does not comprise an autoantibody.

54. A method of killing a cancer cell in a subject in need thereof comprising administering:

a) an inhibitor of an immune-inhibitory protein; and

b) a device comprising

i) a scaffold composition,

ii) a cell recruitment composition, and

iii) a bioactive composition, wherein the bioactive composition is incorporated into or coated onto the scaffold composition, and wherein the bioactive composition causes modification of cells in or recruited to the device.

55. The method of claim 54, wherein the scaffold comprises open, interconnected macropores, and wherein migration of the modified cells to another site in the body is promoted by the open, interconnected macropores and by the deployment signal.

56. The method of claim 55, wherein the other site in the body is a nearby or remote tissue target.

57. The method of claim 54, wherein the inhibitor is present in or on the device.

58. The method of claim 57, wherein the inhibitor is coated in or on the scaffold composition.

59. The method of claim 54, wherein the inhibitor is not present in or on the device.

60. The method of claim 59, wherein the inhibitor is not coated in or on the scaffold composition.

61. The method of claim 54, wherein the inhibitor and the device are formulated together.

62. The method of claim 54, wherein the inhibitor and the device are formulated separately.

63. The method of claim 62, wherein the inhibitor and the device are administered to the subject simultaneously.

64. The method of claim 62, wherein the inhibitor and the device are administered to the subject sequentially.

66. The method of claim 54, wherein the inhibitor is administered intravenously, intraperitoneally, subcutaneously, orally, intradermally, by inhalation, transmucosally, or rectally.

67. The method of claim 54, wherein the inhibitor is administered by injection, infusion, or inhalation.

68. The method of claim 54, wherein the inhibitor is administered at a dosage of 0.01-10 mg/kg bodyweight.

69. The method of claim 54, wherein the inhibitor is administered in an amount of 0.01-30 mg per dose.

74. The method of claim 54, wherein the inhibitor of an immune-inhibitory protein comprises an inhibitor of CTLA4 and an inhibitor of PD1.

75. The method of claim 74, wherein said inhibitor of CTLA4 comprises an anti-CTLA-4 antibody, and wherein said inhibitor of PD1 comprises an anti-PD1 antibody.

76. The method of claim 54, wherein the scaffold comprises a hydrogel or porous polymer, said scaffold comprising a polymer or co-polymer of poly (D,L-lactide-co-glycolide) (PLG).

77. The method of claim 54, wherein cytotoxic T cells are enhanced relative to immunosuppressive Treg cells.

78. The method of claim 54, wherein said inhibitor of an immune-inhibitory protein is administered prior to and subsequent to administration of the device.