Apparatus, system, and method for creating immunologically enhanced spaces in-vivo

• US 8,697,104 B2
• Filed: 03/01/2010
• Issued: 04/15/2014
• Est. Priority Date: 02/28/2009
• Status: Expired due to Fees

• Current Assignee: Charles Knezevich, Robert Silvetz
• Original Assignee: Charles Knezevich, Robert Silvetz
• Inventors: Knezevich, Charles, Silvetz, Robert
• Primary Examiner(s): CANELLA, KAREN A
• Application Number:
  US12/715,052
• Publication Number:
  US 20100272772A1
• Time in Patent Office: 1,506 Days
• Field of Search: None
• US Class Current: 424/422
• CPC Class Codes: A61K 2039/5152 Tumor cells
• CPC Class Codes: A61K 2039/5154 Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
• CPC Class Codes: A61K 2039/60 characteristics by the carrier linked to the antigen
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 39/4615 Dendritic cells
• CPC Class Codes: A61K 39/4622 Antigen presenting cells
• CPC Class Codes: A61K 39/464 characterised by the antigen targeted or presented
• CPC Class Codes: A61K 39/464499 Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 31/005 Ingredients of undetermined constitution or reaction products thereof
• 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

Abstract

The present invention creates an immunologically protected/enhanced space in viva in a mammal by removing the impact of soluble inhibitors of the mammal'"'"'s immune system in a defined space within the body. Placing an antigen source within the defined protected space along with a monocyte-containing blood sample from the mammal being treated and a dendritic cell-inducing factor allows a dendritic-antigen presentation process to proceed to completion. The protected/enhanced space is created by surrounding the protected space with ligands which absorb and/or bind to one or more soluble inhibitors. The implant can be loaded with a patient'"'"'s cancer cells to treat cancer.

Claims

1. A method of creating antigen exposed dendritic cells within an immunologically protected/enhanced space in vivo in a mammal which comprises:

a) removing the impact of soluble inhibitors of the mammal'"'"'s immune system in a defined space within the mammal'"'"'s body;

b) placing dendritic cells, dendritic cell precursors, or monocytes within the defined space; and

c) placing an antigen source within the defined space to allow a dendritic-antigen presentation process to proceed; and

wherein the defined space is created by providing one or more ligands that bind to soluble inhibitors of the mammal'"'"'s immune system.

2. The method of claim 1 wherein the antigen source is one or more bacterial antigens, one or more viral antigens or one or more cancer cell antigens.

3. The method of claim 2 wherein the mammal has a cancer and the one or more cancer antigens are autologous cancer cells harvested from the mammal'"'"'s cancer.

4. The method of claim 1, wherein the ligands bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TNF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R,IL-12R, and erythropoietin receptor.

5. The method of claim 1, wherein the mammal is a human.

6. The method according to claim 1, which comprises:

a) providing an enclosed space within the mammal, said enclosed space comprising an internal region and a peripheral region wherein the peripheral region contains ligands that bind soluble inhibitors of the mammalian immune system;

b) placing within the internal region of the enclosed space;

(i) one or more antigens or cells containing one or more antigens,

(ii) a fraction of the mammal'"'"'s blood that contains dendritic precursor cells, and

(iii) one or more dendritic cell inducing factors;

c) allowing dendritic cells to be induced whereby antigen presentation to said induced dendritic cells proceeds in the substantial absence of soluble inhibitors of the mammal'"'"'s immune system to form activated dendritic cells; and

d) releasing the activated dendritic cells to circulate through the mammal'"'"'s vascular and/or immune system.

7. The method of claim 6 wherein the one or more antigens are one or more bacterial antigens, one or more viral antigens or one or more cancer cell antigens.

8. The method of claim 7 wherein the mammal has a cancer and the one or more cancer antigens are autologous cancer cells harvested from the mammal'"'"'s cancer.

9. The method of claim 8 wherein the ligands bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

10. The method of claim 9 wherein the dendritic cell-inducing factors comprise IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine, an IL-18 cytokine or mixtures thereof.

11. The method of claim 6 wherein the enclosed space is located in subcutaneous tissue.

12. The method of claim 8 wherein the enclosed space is located in subcutaneous tissue.

13. A method of treating a mammal with cancer wherein said method comprises:

a) providing an enclosed space within a mammal, said enclosed space comprising an internal region and a peripheral region wherein the peripheral region contains ligands that bind soluble inhibitors of the mammalian immune system and defines the internal region;

b) placing within the internal region of the enclosed space;

(i) one or more cancer cell antigens or a sample of the mammal'"'"'s cancer cells,

(ii) a fraction of the mammal'"'"'s blood that contains monocyte cells, and

(iii) one or more dendritic cell inducing factors;

c) allowing dendritic cells to be induced from said monocyte cells whereby antigen presentation to said induced dendritic cells proceeds in the substantial absence of soluble inhibitors of the mammal'"'"'s immune system to form activated dendritic cells; and

d) releasing the activated dendritic cells into the mammal'"'"'s vascular and/or immune system.

14. The method of claim 13 wherein the cancer cells are autologous cells harvested from the patient'"'"'s cancer.

15. The method of claim 13 wherein the cancer cells are placed into a chamber having a chamber wall in the internal region wherein said chamber wall is impervious to cells but porous to sub-cellular components.

16. The method of claim 13 wherein ligands that bind with one or more of the soluble inhibitors of the immune system are one or more ligands selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

17. The method of claim 13 wherein the dendritic cell inducing factors comprise IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine, an IL-18 cytokine or mixtures thereof.

18. A method of treating a mammal that has cancer with an implant device which comprises:

a) providing an implant device that contains a protective space for antigen presentation to dendritic cells wherein said protective space is surrounded by a soluble inhibitor adsorbent;

b) placing one or more antigens or cells containing one or more antigens into the protective space of the implant device;

c) placing a leukocyte fraction of blood obtained from the mammal and one or more dendritic cell inducing factors into the protective space of the implant device to induce formation of dendritic cells to form a loaded implant device;

d) inserting the loaded implant device into the mammal; and

e) releasing the induced dendritic cells from the implant into the mammal'"'"'s vascular and/or immune system,

whereby the soluble inhibitor adsorbent allows antigen presentation to the induced dendritic cells to proceed.

19. The method of claim 18 wherein the one or more antigens are one or more bacterial antigens, one or more viral antigens or one or more cancer cell antigens.

20. The method of claim 19 wherein the one or more cancer antigens are autologous cancer cells harvested from the mammal'"'"'s cancer.

21. The method of claim 20 wherein the soluble inhibitor adsorbent comprises one or more ligands that bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

22. The method of claim 18 wherein the dendritic cell-inducing factors comprise IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine, an IL-18 cytokine or mixtures thereof.

23. The method of claim 18 wherein the loaded implant is inserted through an incision in the skin into a subcutaneous tissue.

24. The method of claim 18 wherein the loaded implant is inserted into subcutaneous tissue with a needle and syringe.

25. A method of treating a patient that has cancer with an implant device which comprises:

a) providing an implant device that contains a protective space for cancer antigen presentation to dendritic cells wherein said protective space is surrounded by a soluble inhibitor adsorbent;

b) placing one or more cancer antigens or cancer cells into the protective space of the implant device;

c) placing a leukocyte fraction of a blood sample obtained from the patient and one or more dendritic cell-inducing factors into the protective space of the implant device to induce formation of dendritic cells to form a loaded implant device;

d) inserting the loaded implant device into the patient; and

e) releasing the formed dendritic cells from the implant into the patient'"'"'s vascular and/or immune system;

whereby the soluble inhibitor adsorbent allows antigen presentation to the induced dendritic cells to proceed.

26. The method of claim 25 wherein the cancer cells are autologous cells harvested from the patient'"'"'s cancer.

27. The method of claim 25 wherein the cancer cells are placed into a chamber having a chamber wall in the protective space wherein said chamber wall is impervious to cells but porous to sub-cellular components.

28. The method of claim 25 wherein the implant device comprises polymeric components that are impervious to cells but porous to sub-cellular components.

29. The method of claim 25 wherein the loaded implant device is inserted through an incision in the skin into subcutaneous tissue.

30. The method of claim 25 wherein the loaded implant device is inserted into subcutaneous tissue with a needle and syringe.

31. The method of claim 25 wherein the soluble inhibitor adsorbent comprises one or more ligands that bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R,IL-12R, and erythropoietin receptor.

32. The method of claim 25 wherein the dendritic cell inducing factors comprise IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine, an IL-18 cytokine or mixtures thereof.

33. A medical implant device for mammals which comprises:

a) a porous biocompatible outer case and

b) an immunologically protected/enhanced inner space that contains

(i) one or more antigens,

(ii) one or more dendritic cell-inducing factors,

(iii) a leukocyte fraction of a blood sample from a mammal who is the intended recipient of the medical implant device, and

(iv) an adsorbent of soluble inhibitors to a mammalian immune system and

c) a biodegradable plug.

34. The medical implant device of claim 33 wherein the one or more antigens are bacterial antigens, viral antigens or cancer cell antigens.

35. The medical implant device of claim 34 wherein the mammal has a cancer and the one or more antigens are autologous cancer cells harvested from the mammal'"'"'s cancer.

36. The medical implant device of claim 34 wherein the cancer cells are placed into a chamber in the immunologically protected inner space wherein said chamber is impervious to cells but porous to sub-cellular components.

37. The medical implant device of claim 33 wherein the porous biocompatible outer case comprises polymeric components that are impervious to cells but porous to sub-cellular components.

38. The medical implant device of claim 33 wherein the implant device is configured for administration by insertion through an incision in the skin into subcutaneous tissue.

39. The medical implant device of claim 33 wherein the implant device is configured for administration by insertion into subcutaneous tissue with a needle and syringe.

40. The medical implant device of claim 33 wherein the adsorbent of soluble inhibitors comprises one or more ligands that bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

41. The medical implant device of claim 33 wherein the one or more dendritic cell inducing factors are selected from the group consisting of IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine and an IL-18 cytokine.

42. A medical implant device to produce an immune response to an antigen in a mammal which comprises:

a) a porous outer biocompatible case,

b) a peripheral region within the biocompatible case that contains ligands which bind to soluble inhibitors to a mammalian immune system,

c) an inner region which contains one or more antigens, a leukocyte fraction of a blood sample from the mammal to be treated and one or more dendritic cell inducing factors and

d) a biodegradable plug,

wherein the peripheral region and the inner region are separated by a membrane that is porous to cytokines and cytokine receptors but not to cells.

43. The medical implant device of claim 42 wherein the one or more antigens are bacterial antigens, viral antigens or cancer cell antigens.

44. The medical implant device of claim 43 wherein the cancer cell antigens are autologous cancer cells harvested from the mammal to be treated with said medical implant device.

45. The medical implant device of claim 44 wherein the cancer cells are placed into a chamber in the inner region wherein said chamber is impervious to cells but porous to sub-cellular components.

46. The medical implant device of claim 42 wherein the implant device is configured for administration by insertion through an incision into subcutaneous tissue.

47. The medical implant device of claim 42 wherein the implant device is configured for administration by insertion into subcutaneous tissue with a needle and syringe.

48. The medical implant device of claim 42 wherein the ligands bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

49. The medical implant device of claim 42 wherein the one or more dendritic cell inducing factors are selected from the group consisting of IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine and an IL-18 cytokine.

50. A medical implant device for mammals which comprises:

a) a biocompatible outer case that allows flow of blood into the implant device when implanted into a mammal and

b) an immunologically protected inner space which contains

(i) one or more antigens,

(ii) dendritic cells and/or monocytes,

(iii) a leukocyte attractant, and

(iv) an adsorbent of soluble inhibitors to a mammalian immune system

whereby a dendritic cell-antigen presentation process is able to proceed sufficiently to form activated dendritic cells.

51. The medical implant device of claim 50 wherein the one or more antigens are bacterial antigens, viral antigens or cancer cell antigens.

52. The medical implant device of claim 51 wherein the cancer cell antigens are autologous cancer cells harvested from the mammal to be treated with said medical implant device.

53. Inc medical implant device of claim 52 wherein the cancer cells are placed into a chamber in the immunologically protected inner space wherein said chamber is impervious to cells but porous to sub-cellular components.

54. The medical implant device of claim 50 wherein the implant device is configured for administration by insertion through an incision into subcutaneous tissue.

55. The medical implant device of claim 50 wherein the implant device is configured for administration by insertion into subcutaneous tissue with a needle and syringe.

56. The medical implant device of claim 50 wherein the adsorbent of soluble inhibitors comprises one or more ligands that bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

57. A medical implant device to treat cancer in a mammal which comprises:

a) a porous outer biocompatible case,

b) a peripheral region within the biocompatible case that contains ligands which bind to soluble inhibitors to a mammalian immune system,

c) an inner region which contains cancer antigens and a leukocyte fraction of a blood sample from the mammal to be treated for cancer, and

d) a biodegradable plug

wherein the peripheral region and the inner region are separated by a membrane that is porous to cytokines and cytokine receptors but impervious to cells.

58. The medical implant device of claim 57 wherein the cancer antigens are autologous cancer cells harvested from the mammal'"'"'s cancer.

59. The medical implant device of claim 58 wherein the cancer cells are placed into a chamber in the inner region wherein said chamber wall is impervious to cells but porous to sub-cellular components.

60. The medical implant device of claim 57 wherein the porous outer biocompatible case comprises polymeric components that are impervious to cells but porous to sub-cellular components.

61. The medical implant device of claim 57 wherein the implant device is configured for administration by insertion through an incision into subcutaneous tissue.

62. The medical implant device of claim 57 wherein the implant device is configured for administration by insertion into subcutaneous tissue with a needle and syringe.

63. The medical implant device of claim 57 wherein the ligands bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R,IL-12R, and erythropoietin receptor.

64. The medical implant device of claim 57 further comprising one or more dendritic cell inducing factors selected from the group consisting of IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine and an IL-18 cytokine.

65. A medical implant pellet to treat cancer in a mammal that can be administered with a needle and syringe which comprises:

a) a porous outer biocompatible case,

b) a peripheral region within the biocompatible case that contains ligands which bind to soluble inhibitors to a mammalian immune system,

c) an inner region which contains cancer antigens, a leukocyte fraction of a blood sample from the mammal to be treated for cancer and one or more dendritic cell inducing factors, and

d) a biodegradable plug wherein the peripheral region and the inner region are separated by a membrane that is porous to cytokines and cytokine receptors but impervious to cells.

66. The medical implant pellet of claim 65 which is cylindrical in shape and has an outside diameter of between 0.5 and 2 mm.

67. The medical implant pellet of claim 65 wherein the cancer antigens are autologous cancer cells harvested from the mammal to be treated.

68. The medical implant pellet of claim 65 wherein the cancer cells are placed into a chamber in the inner region wherein said chamber is impervious to cells but porous to sub-cellular components.

69. The medical implant pellet of claim 65 wherein the porous outer biocompatible case comprises polymeric components that are impervious to cells but porous to sub-cellular components.

70. The medical implant pellet of claim 65 wherein the medical implant pellet is configured for administration by insertion into subcutaneous tissue with a needle and syringe.

71. The medical implant pellet of claim 65 wherein the ligands bind with one or more of the soluble inhibitors of the immune system selected from the group consisting of gangliosides, growth factors, TGF-alpha, TGF-beta and variants thereof, PDGF, EGF, IGF and variants thereof, FGF and variants thereof, VEGF, inflammatory cytokine receptors selected from the group consisting of the TNF-alpha family:

TNF-R1, TNF-R2, CD40L, NGFR, TRAIL and variants, FASL, IL-1R1, IL1R2, IL-2R, IL-3R, IL-5R, IL-6R, IL-7R, GM-CSFR, IL-9R, IL-12R, and erythropoietin receptor.

72. The medical implant pellet of claim 65 wherein the one or more dendritic cell inducing factors are selected from the group consisting of IL-4, GM-CSF, IL-10, IL-13, an IL-17 cytokine and an IL-18 cytokine.