Method for stimulating a host immune system
A method of manipulating allogeneic cells for use in allogeneic cell therapy protocols is described. The method provides a composition of highly activated allogeneic T-cells which are infused into immunocompetent cancer patients to elicit a novel anti-tumor immune mechanism called the “Mirror Effect”. In contrast to current allogeneic cell therapy protocols where T-cells in the graft mediate the beneficial graft vs. tumor (GVT) and detrimental graft vs. host (GVH) effects, the allogeneic cells of the present invention stimulate host T-cells to mediate the “mirror” of these effects. The mirror of the GVT effect is the host vs. tumor (HVT) effect. The “mirror” of the GVH effect is the host vs. graft (HVG) effect. The effectiveness and widespread application of the anti-tumor GVT effect is limited by the severe toxicity of the GVH effect. In the present invention, the anti-tumor HVT effect occurs in conjunction with a non-toxic HVG rejection effect. The highly activated allogeneic cells of the invention can be used in methods to stimulate host immunity. The method includes a complete HLA mis-matched setting in patients that have not had a prior bone marrow transplant or received chemotherapy and/or radiation conditioning regimens.
1. A method for stimulating a host immune system, the method comprising:
(a) Collecting mononuclear cells from a donor;
(b) Activating T-cells within said mononuclear cells ex-vivo;
(c) Administering said activated T-cells to a host having a host immune system, whereby the activated T-cells are rejected by the host immune system while stimulating the host immune system to mediate an effective immune response.
2. The method of claim 1 wherein said host has cancer.
3. The method of claim 2 wherein said host has a hematological malignancy.
4. The method of claim 2 wherein said cancer is a solid tumor.
5. The method of claim 4 wherein said solid tumor has metastasized.
6. The method of claim 1 wherein said donor is selected without regard to histocompatibility to said host.
7. The method of claim 1 wherein said donor is selected for maximum histocompatibility mis-match with said host.
8. The method of claim 1 wherein said host has not had a prior bone marrow transplant procedure.
9. The method of claim 1 wherein said host has not received any immunosuppressive chemotherapy and/or radiation conditioning regimens designed to allow engraftment of allogeneic donor cell infusions.
10. The method of claim 1 wherein said T-cells are CD4+ T-cells.
11. The method of claim 10 wherein a majority of said CD4+ T-cells differentiate after ex-vivo activation from CD45RA+, CD62L hi naïve cells into CD45RO+, CD62L lo memory cells.
12. The method of claim 11 wherein said CD4+ T-cells produce at least one of the following cytokines: IL-2, IFN-gamma, TNF-alpha.
13. The method of claim 10 wherein said CD4+ T-cells after ex-vivo activation express CD40L and/or TRAIL on the cell surface.
14. The method of claim 1 wherein said T-cells are activated by cross-linking of anti-CD3 and anti-CD28 mAbs applied to the cell surface of the T-cells.
15. The method of claim 1 wherein greater than 90% of the T-cells are activated at the time of administration to the host and just prior to contacting the host immune system.
16. The method of claim 1 wherein greater than 95% of the T-cells are activated at the time of administration to the host and just prior to contacting the host immune system.
17. The method of claim 14 wherein said anti-CD3 and anti-CD28 mAbs applied to the surface of said T-cells are cross-linked by association with biodegradable microspheres coated with an agent reactive against said mAbs.
18. The method of claim 1 wherein said T-cells are continuously exposed to an activating stimulus for at least 6 days.
19. The method of claim 1 wherein said T-cells are activated while being maintained at cell densities of at least 10 7 cells/ml to maximize cell to cell contact.
20. The method of claim 18 wherein said T-cells are activated while being maintained at cell densities of at least 10 7 cells/ml to maximize cell to cell contact.
21. The method of claim 1 wherein said T-cells are administered with anti-CD3 and anti-CD28 mAbs applied to the surface of the T-cells and wherein said mAbs are cross-linked by association with and inclusion of biodegradable microspheres coated with an agent reactive against said mAbs.
22. The method of claim 1 wherein said activated T-cell administration stimulates production of Type 1 cytokines.
23. The method of claim 22 wherein said Type 1 cytokines include at least one of the following: IL-1, IL-2, IL-12, IL-15, IFN-gamma, IFN-alpha, IFN-beta, TNF-alpha, and TNF-beta.
24. The method of claim 22 wherein said Type 1 cytokines stimulates host innate immune function.
25. The method of claim 1 wherein said activated T-cell administration activates host dendritic and/or macrophage cells.
26. The method of claim 1 wherein said activated T-cell administration and subsequent rejection of said activated T-cells stimulates an immune response against a host resident disease.
27. The method of claim 1 wherein said ex-vivo activated T-cells are cryopreserved prior to administration to the host.
28. A method for stimulating a host immune system, the method comprising administering activated T-cells to a host having a host immune system, the T-cells derived from mononuclear cells collected from a donor and activated ex-vivo, whereby the activated T-cells are rejected by the host immune system while stimulating the host immune system to mediate an effective immune response.
29. The method of claim 28 wherein said donor is selected without regard to histocompatibility to said host.
30. The method of claim 28 wherein said host has not received any immunosuppressive chemotherapy and/or radiation conditioning regimens designed to allow engraftment of allogeneic donor cell infusions.
31. The method of claim 28 wherein said T-cells are administered with anti-CD3 and anti-CD28 mAbs applied to the surface of the T-cells and wherein said mAbs are cross-linked by association with and inclusion of biodegradable microspheres coated with an agent reactive against said mAbs.
32. The method of claim 28 wherein said activated T-cell administration stimulates production of Type 1 cytokines.
33. The method of claim 32 wherein said Type 1 cytokines stimulates host innate immune function.
34. The method of claim 28 wherein said activated T-cell administration and subsequent rejection of said activated T-cells stimulates an immune response against a host resident disease.