Conditioning protocols for use with Anti-viral central memory cd8+veto cells in haploidentical stem cell transplantation
A conditioning regimen using bone marrow irradiation, immature hematopoietic cell transplantation, and suppressor cells effectively addresses the challenge of managing pathological cells in bone marrow during haploidentical stem cell transplantation, improving transplant success and reducing graft-versus-host disease.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- YEDA RES & DEV CO LTD
- Filing Date
- 2026-03-09
- Publication Date
- 2026-07-10
AI Technical Summary
Current methods for haploidentical stem cell transplantation are inadequate in effectively managing pathological cells in bone marrow, necessitating a more effective conditioning regimen to enhance transplant success and reduce graft-versus-host disease.
A method involving whole bone marrow irradiation, T-cell-depleted immature hematopoietic cell transplantation, cyclophosphamide administration, and suppressor non-graft-anti-host disease inducing cells to treat diseases with pathological cells in bone marrow.
Enhances transplant success and reduces graft-versus-host disease by conditioning the subject with a comprehensive regimen that includes bone marrow irradiation, immature hematopoietic cell transplantation, and suppressor cell administration.
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Abstract
Description
{PURLE-26016-HKSPT / 02496762v1} Summary of a conditioning regimen in haploidentical stem cell transplantation combined with antiviral central memory CD8+ suppressor cells provides a conditioning regimen in haploidentical stem cell transplantation combined with antiviral central memory CD8+ suppressor cells. Therefore, a method is provided for treating a disease in a subject with this need, wherein the disease includes pathological cells present in the subject's bone marrow. The method includes: conditioning the subject under a pre-transplant conditioning regimen comprising whole bone marrow irradiation; transplanting T-cell-depleted immature hematopoietic cells into the subject; administering cyclophosphamide to the subject; and administering suppressor non-graft-anti-host disease inducing cells to the subject.
Claims
WHAT IS CLAIMED IS:
1. A method of treating a disease in a subject in need thereof, wherein said disease comprises pathological cells residing in a bone marrow of said subject, the method comprising:(a) conditioning the subject under a pre-transplant conditioning protocol comprising a therapeutically effective amount of total marrow irradiation (TMI); and subsequently(b) transplanting into said subject therapeutically effective amount of T cell depleted immature hematopoietic cells; and subsequently(c) administering to said subject a therapeutically effective amount of cyclophosphamide; and subsequently(d) administering to said subject a therapeutically effective amount of veto non-graft versus host disease (GVHD) inducing cells, thereby treating the disease in the subject.
2. A combination of pre-transplant conditioning protocol comprising a therapeutically effective amount of total marrow irradiation (TMI), a therapeutically effective amount of T cell depleted immature hematopoietic cells, a therapeutically effective amount of cyclophosphamide and a therapeutically effective amount of veto non-graft versus host disease (GVHD) inducing cells for use in treating a disease in a subject in need thereof, wherein said disease comprises pathological cells residing in a bone marrow of said subject.
3. The method of claim 1 or the combination for use of claim 2, wherein said disease is cancer.
4. The method or the combination for use of claim 3, wherein said cancer comprises a myeloid malignancy or multiple myeloma.
5. The method or the combination for use of claim 4, wherein said myeloid malignancy is selected from the group consisting of AML, CML and MDS.
6. The method or the combination for use of claim 3, wherein said cancer comprises AML or MDS.
7. The method of claim 1 or the combination for use of claim 2, wherein said disease is non-cancerous.
8. The method or the combination for use of claim 7, wherein said disease is selected from the group consisting of sickle cell anemia, aplastic anemia, thalassemia and metabolic genetic disease.
9. The method or the combination for use of any one of claims 1-8, wherein said veto non-GVHD inducing cells are obtained from the same donor as said T cell depleted immature hematopoietic cells.
10. The method or the combination for use of any one of claims 1-9, wherein said conditioning further comprises a therapeutically effective amount of spleen irradiation.
11. The method or the combination for use of any one of claims 1-10, wherein said TMI is administered on days -7 to -1 prior to transplantation of said T cell depleted immature hematopoietic cells.
12. The method or the combination for use of any one of claims 1-11, wherein said therapeutically effective amount of said TMI comprises a total of 8-18 Gy.
13. The method or the combination for use of any one of claims 1-12, wherein said therapeutically effective amount of said TMI is administered in at least 2 doses administered on consecutive days.
14. The method or the combination for use of any one of claims 1-13, wherein said therapeutically effective amount of said TMI is administered in 4 doses administered on consecutive days.
15. The method or the combination for use of any one of claims 1-14, wherein said T cell depleted immature hematopoietic cells are derived from a donor non-syngeneic to said subject.
16. The method or the combination for use of claim 15, wherein said non-syngeneic is allogeneic.
17. The method or the combination for use of claim 16, wherein said allogeneic donor is an HLA matched sibling, an HLA matched unrelated donor, an HLA haploidentical related donor or a donor displaying one or more disparate HLA determinants.
18. The method or the combination for use of any one of claims 1-17, wherein said therapeutically effective amount of said T cell depleted immature hematopoietic cells comprises less than 5 x 105CD3+T cells per kilogram ideal body weight of said subject.
19. The method or the combination for use of any one of claims 1-17, wherein said therapeutically effective amount of said T cell depleted immature hematopoietic cells comprises less than 2 x 105CD3+T cells per kilogram ideal body weight of said subject.
20. The method or the combination for use of any one of claims 1-19, wherein said therapeutically effective amount of said T cell depleted immature hematopoietic cells comprises at least 5 x 106CD34+cells per kilogram ideal body weight of said subject.
21. The method or the combination for use of any one of claims 1-20, wherein said therapeutically effective amount of said T cell depleted immature hematopoietic cells are depleted of CD3+and / or CD19+expressing cells.
22. The method or the combination for use of any one of claims 1-21, wherein said therapeutically effective amount of said cyclophosphamide comprises 25-200 mg cyclophosphamide per kilogram ideal body weight of said subject.
23. The method or the combination for use of any one of claims 1-22, wherein said therapeutically effective amount of said cyclophosphamide is administered to said subject in two doses between days 2 and 5 following said transplantation of said T cell depleted immature hematopoietic cells.
24. The method or the combination for use of any one of claims 1-22, wherein said therapeutically effective amount of said cyclophosphamide is administered to said subject in two doses 3 and 4 days following said transplantation of said T cell depleted immature hematopoietic cells.
25. The method or the combination for use of any one of claims 1-24, wherein said veto non-GVHD inducing cells comprise a central memory T-lymphocyte (Tcm) phenotype.
26. The method or the combination for use of any one of claims 1-25, wherein said veto non-GVHD inducing cells have an anti-viral activity.
27. The method or the combination for use of any one of claims 1-26, wherein said veto non-GVHD inducing cells are obtainable by:(i) contacting a first population of peripheral blood mononuclear cells (PBMCs) from a donor with an antibody capable of binding CD14+expressing cells and selecting CD14+expressing cells capable of maturing into antigen presenting cells;(ii) loading said antigen presenting cells with a viral peptide;(iii) treating a second population of PBMCs of the same donor as said first population of PBMCs with one or more agents capable of depleting CD4+, CD56+and CD45RA+expressing cells so as to obtain a population of cells comprising T cells enriched in memory T cells expressing a CD45RA CD8+phenotype;(iv) contacting said population of cells comprising said T cells enriched in said memory T cells with said antigen presenting cells loaded with said viral peptides of step (ii) in the presence of IL-21 so as to allow enrichment of viral reactive memory T cells; and(v) culturing said cells resulting from step (iv) in the presence of IL-21, IL- 15 and / or IL- 7 so as to allow proliferation of cells comprising said Tcm phenotype.
28. The method or the combination for use of any one of claims 1-27, wherein said therapeutically effective amount of said veto non-GVHD inducing cells is administered on day 6-9 following said transplantation of said T cell depleted immature hematopoietic cells.
29. The method or the combination for use of any one of claims 1-28, wherein said therapeutically effective amount of said veto non-GVHD inducing cells comprises at least 2.5 x 106CD8+cells per kg ideal body weight of said subject.
30. The method or the combination for use of any one of claims 1-29, wherein said subject is not treated chronically with GVHD prophylaxis following said transplantation.
31. The method or the combination for use of any one of claims 1-30, wherein said conditioning further comprises an anti-B cell therapy.
32. The method or the combination for use of claim 31, wherein said anti-B cell therapy comprises an anti-B cell antibody.
33. The method or the combination for use of any one of claims 31-32, wherein said anti- B cell therapy comprises Rituximab.
34. The method or the combination for use of any one of claims 1-33, wherein said conditioning further comprises T cell debulking.
35. The method or the combination for use of claim 34, wherein said T cell debulking is effected by antibodies, and optionally wherein said antibodies comprise at least one of an antithymocyte globulin (ATG) antibody, an anti-CD52 antibody and anti-CD3 antibody.
36. The method or the combination for use of claim 34, wherein said T cell debulking is effected by an anti-thymocyte globulin (ATG) antibody.
37. The method or the combination for use of any one of claims 1-36, wherein said conditioning further comprises a chemotherapeutic agent.
38. The method or the combination for use of claim 37, wherein said chemotherapeutic agent comprises at least one of Fludarabine, Busulfan, Melphalan, Thiotepa and cyclophosphamide.
39. The method or the combination for use of claim 37, wherein said chemotherapeutic agent comprises Fludarabine.