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1. (WO2019028422) METHODS FOR ACTIVATING IMMUNE CELLS
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WHAT IS CLAIMED IS:

1. A method for activating an immune cell in a subject, the method comprising:

(a) passing an immune cell from the subject through an immune modulating chamber, wherein the immune modulating chamber comprises a solid support and a tumor cell that is restrained on the solid support within the immune modulating chamber, thereby exposing the immune cell to the tumor cell and activating the immune cell, and

(b) returning the activated immune cell to the subject.

2. The method of claim 1, wherein the method is performed ex vivo.

3. The method of claim 1 or 2, wherein the method increases an autologous immune response in the subject.

4. The method of any one of claims 1 to 3, wherein the method reduces or eliminates an adverse effect of a systemic therapy in the subject.

5. The method of any one of claims 1 to 4, wherein the immune cell is a leukocyte or peripheral blood mononuclear cell (PBMC).

6. The method of method of any one of claims 1 to 5, wherein the immune modulating chamber further comprises a stromal cell and/or a stromal component that is restrained on the solid support.

7. The method of any one of claims 1 to 6, wherein the immune cell is contained within a whole blood sample that is obtained from the subject.

8. The method of claim 7, wherein the whole blood sample is passed through the immune modulating chamber.

9. The method of claim 7, wherein an immune cell-containing portion is isolated from the whole blood sample, and the immune cell-containing portion of the whole blood sample is passed through the immune modulating chamber.

10. The method of claim 9, wherein the immune cell-containing portion of the whole blood sample is isolated using a filtration method.

11. The method of claim 9, wherein the immune cell-containing portion of the whole blood sample is isolated using apheresis.

12. The method of any one of claims 9 to 11, wherein the immune cell-containing portion of the whole blood sample is isolated by passing the whole blood sample through an isolation device that is in fluid communication with the immune modulating chamber.

13. The method of any one of claims 9 to 12, wherein an immune inhibition factor and/or a factor that has an adverse effect on the subject are removed from the immune cell-containing portion and/or a non-immune cell-containing portion of the whole blood sample before the immune cell-containing portion and/or the non-immune cell-containing portion of the whole blood sample are returned to the subject.

14. The method of any one of claims 1 to 13, wherein the immune modulating chamber further comprises an inlet port and/or an outlet port.

15. The method of claim 14, wherein the inlet and/or the outlet port are in fluid communication with the subject's vascular system, peritoneal cavity, pleural cavity, or cerebrospinal fluid (CSF).

16. The method of claim 15, wherein the inlet and/or outlet port are in fluid communication with the subject's venous system.

17. The method of claim 15, wherein the inlet and/or outlet port are in fluid communication with the subject's arterial system.

18. The method of any one of claims 1 to 17, wherein the tumor cell is a circulating tumor cell (CTC).

19. The method of any one of claims 1 to 18, wherein the tumor cell comprises a tumor cell lysate.

20. The method of any one of claims 1 to 19, wherein the tumor cell comprises a plurality of tumor cells.

21. The method of any one of claims 1 to 20, wherein the tumor cell is obtained from a biopsy, a fine needle aspirate (FNA), a surgical resection, a blood sample, a pleural effusion sample, a peritoneal effusion sample, a CSF sample, or a combination thereof.

22. The method of any one of claims 1 to 21, wherein the tumor cell comprises an autologous tumor cell and/or an autologous tumor cell lysate.

23. The method of any one of claims 1 to 21, wherein the tumor cell comprises an allogeneic tumor cell and/or an allogeneic tumor cell lysate.

24. The method of any one of claims 1 to 23, wherein the tumor cell is introduced into the immune modulating chamber before the immune cell is passed through the immune modulating chamber.

25. The method of any one of claims 1 to 23, wherein the tumor cell is introduced into the immune modulating chamber concurrently with or after the immune cell is passed through the immune modulating chamber.

26. The method of claim 25, wherein the tumor cell is contained within a whole blood sample or immune cell-containing portion thereof, and becomes restrained on the solid support within the immune modulating chamber as the blood sample or immune cell-containing portion thereof passes through the immune modulating chamber.

27. The method of any one of claims 1 to 26, wherein the tumor and/or stromal cell are restrained on the solid support by a capture moiety.

28. The method of method of claim 27, wherein the capture moiety also promotes tumor and/or stromal cell proliferation.

29. The method of claim 27 or 28, wherein the capture moiety is selected from the group consisting of an antibody, a cell adhesion molecule, and a combination thereof.

30. The method of claim 29, wherein the antibody is an antibody that binds to epithelial cell adhesion molecule (EpCAM), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), MUCl, CD44, HER2, HER3, FGFRl, FGFR2, FGFR3, FGFR4, IGF1R, c-Met, EGFR, PD-L1, or a combination thereof.

31. The method of claim 29, wherein the cell adhesion molecule is selected from the group consisting of a selectin, an integrin, vascular cell adhesion molecule 1 (VCAMl), and a combination thereof.

32. The method of claim 31, wherein the selectin is selected from the group consisting of E-selectin, L-selectin, and a combination thereof.

33. The method of any one of claims 1 to 32, wherein the immune modulating chamber further comprises a pro-immunogenic factor.

34. The method of claim 33, wherein the pro-immunogenic factor is an immune stimulating factor, an anti-immune inhibition factor, or a combination thereof.

35. The method of claim 34, wherein the immune stimulating factor is selected from the group consisting of interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin- 12 (IL-12), interleukin 17 (IL-17), interleukin 22 (IL-22), C-X-C chemokine receptor type 3 (CXCR3), interferon gamma (INFy), tumor necrosis factor alpha (TNFa), granulocyte-macrophage colony-stimulating factor (GM-CSF), and a combination thereof.

36. The method of claim 34 or 35, wherein the immune stimulating factor is IL-2.

37. The method of claim 34, wherein the anti-immune inhibition factor is selected from the group consisting of an immune checkpoint inhibitor, an indoleamine 2,3-dioxygnease (IDO) inhibitor, and a combination thereof.

38. The method of claim 37, wherein the immune checkpoint inhibitor inhibits programmed cell death 1 ligand 1 (PDLl), programmed cell death protein 1 (PDl), cytotoxic T lymphocyte associated protein 4 (CTLA4), T cell immunoglobulin 3 (TFM3), lymphocyte activation gene 3 (LAG3), V-domain Ig suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), or a combination thereof.

39. The method of any one of claims 1 to 38, wherein the immune modulating chamber further comprises a subject-specific mutated peptide.

40. The method of claim 39, wherein the subject-specific mutated peptide is selected from the group consisting of EGFRvIII peptide, p95HER2 peptide, an EGFR peptide comprising an activating mutation, and a combination thereof.

41. The method of any one of claims 27 to 40, wherein the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide are attached to the solid support.

42. The method of any one of claims 1 to 41, wherein the solid support comprises an interior surface of the immune modulating chamber or a support structure that is in contact with an interior surface of the immune modulating chamber, and optionally further comprises a magnetic composition.

43. The method of claim 42, wherein the support structure comprises a matrix.

44. The method of any one of claims 41 to 43, wherein the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide are covalently attached to the solid support.

45. The method of any one of claims 41 to 43, wherein the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide are magnetically attached to the solid support.

46. The method of claim 45, wherein the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide comprise a magnetic particle.

47. The method of claim 45 or 46, wherein the solid support comprises a magnetic composition and the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide are magnetically attached to the magnetic composition.

48. The method of claim 45 or 46, wherein an electromagnetic field that is external to the immune modulating chamber is used to magnetically attach the capture moiety, pro-immunogenic factor, and/or subject-specific mutated peptide to the solid support.

49. The method of any one of claims 1 to 48, wherein the tumor cell is induced to undergo apoptosis by exposure to an oncolytic virus, radiation, and/or a chemotherapeutic agent.

50. The method of any one of claims 1 to 49, wherein the subject is administered a chimeric antigen receptor T-cell.

51. The method of any one of claims 1 to 50, wherein the immune modulating chamber further comprises a flow regulator.

52. The method of any one of claims 1 to 51, wherein the immune modulating chamber further comprises a pump.

53. The method of claim 51 or 52, wherein the flow regulator and/or the pump are used to adjust the rate at which the immune cell passes through the immune modulating chamber.

54. The method of any one of claims 51 to 53, wherein the availability of oxygen inside the immune modulating chamber is controlled by using the flow regulator and/or the pump to adjust the flow rate of whole blood through the immune modulating chamber and/or by adjusting the number or density of red blood cells passing through the immune modulating chamber.

55. The method of any one of claims 1 to 54, wherein multiple immune modulating chambers are used.

56. The method of claim 55, wherein the multiple immune modulating chambers are each in fluid communication with each other.

57. The method of claim 55 or 56, wherein each of the multiple immune modulating chambers comprises a different tumor cell.

58. The method of any one of claims 1 to 57, wherein a first immune modulating chamber is replaced with a second immune modulating chamber.

59. The method of any one of claims 1 to 58, wherein the tumor cell is removed from the immune modulating chamber after the immune cell has passed through the immune modulating chamber, and the presence or level of one or more biomarkers in the tumor cell is detected.

60. The method of claim 59, wherein the presence or level of the one or more biomarkers is used to provide a diagnosis to the subject and/or select a treatment for a disease in the subject.

61. A method for treating cancer in a subject, the method comprising activating an immune cell according to the method of any one of claims 1 to 60.

62. The method of claim 61, wherein the cancer comprises a solid tumor.

63. The method of claim 61 or 62, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, melanoma, a sarcoma, and a combination thereof.

64. A method for inducing an immune response against a tumor in a subject, the method comprising activating an immune cell according to the method of any one of claims 1 to 60.

65. The method of claim 64, wherein the tumor comprises the same type of tumor cell that is restrained on the solid support within the immune modulating chamber.

66. The method of claim 64 or 65, wherein the tumor is a solid tumor.

67. The method of any one of claims 64 to 66, wherein the tumor is from a cancer selected from the group consisting of lung cancer, brain cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, melanoma, a sarcoma, and a combination thereof.