CN-121985953-A - Three-wire therapy for the treatment of GvHD

Abstract

The present disclosure relates to mesenchymal lineage precursors or stem cell-mediated methods for treating severe graft versus host disease (GvHD) in a subject that is non-responsive to at least two previous treatment lines.

Inventors

• S. Itsku
• J. HAYES

Assignees

• 迈索布拉斯特国际有限公司

Dates

Publication Date

20260505

Application Date

20240828

Priority Date

20230828

Claims (20)

1. 1. A method of treating graft versus host disease (GvHD) in a human subject in need thereof, the method comprising administering to the subject a composition comprising mesenchymal lineage precursors or stem cells (MLPSC), wherein MLPSC is administered to the subject as a trilinear treatment.
2. 2. A method for treating graft versus host disease (GvHD) in a human subject, the method comprising: i) Selecting a subject having GvHD and having failed the second line treatment; ii) administering to the subject a composition comprising mesenchymal lineage precursors or stem cells (MLPSC), wherein MLPSC is administered to the subject as a trilinear treatment.
3. 3. The method of claim 1 or claim 2, wherein the subject is non-responsive to corticosteroid and second line treatment.
4. 4. The method of claim 3, wherein the two-wire treatment is ponatinib.
5. 5. The method of claim 3, wherein the two-wire treatment is a biologic.
6. 6. The method of claim 5, wherein the biological agent is alemtuzumab, basiliximab, or tolizumab.
7. 7. The method according to any one of claims 1 to 6, wherein MLPSC in the composition inhibits IL2-Rα expression by ≡60%, wherein inhibition of IL2-Rα expression is determined by obtaining a cell population comprising MLPSC that is culture expanded, cryopreserved and thawed, co-culturing MLPSC with a cell population comprising T cells in a culture medium, and determining the level of inhibition of IL2-Rα expression.
8. 8. The method of any one of claims 1-7, wherein treatment reduces the risk of mortality in the subject.
9. 9. The method of claim 8, wherein the death is 6 months non-recurrent death (NRM).
10. 10. The method of any one of claims 1-9, wherein the subject is a pediatric subject.
11. 11. The method of any one of claims 1 to 9, wherein the subject is ≡12 years old.
12. 12. The method of any one of claims 1 to 11, wherein the subject has acute graft versus host disease (aGvHD).
13. 13. The method of any one of claims 1 to 12, wherein the subject is classified as one or more of: -grade B, grade C or grade D according to IBMTR severity scale; Grade II GvHD according to Glucksberg severity scale; grade III/IV GvHD according to Glucksberg severity scale; Minnesota high risk GvHD.
14. 14. The method of any one of claims 1 to 13, wherein the subject has chronic GvHD.
15. 15. The method of any one of claims 1-14, wherein the subject has multiple organ involvement.
16. 16. The method of any one of claims 1 to 15, wherein the subject has Inflammatory Bowel Disease (IBD).
17. 17. The method of claim 16, wherein the IBD is crohn's disease or ulcerative colitis.
18. 18. The method of claim 16, wherein the IBD is crohn's disease.
19. 19. The method of claim 18, wherein the crohn's disease occurs in the rectum and/or colon of the subject.
20. 20. The method of any one of claims 16-19, wherein the IBD of the subject is non-responsive to one or more of adalimumab, cetuzumab, vedolizumab, or Wu Sinu mab.

Description

Three-wire therapy for the treatment of GvHD Technical Field The present disclosure relates to mesenchymal lineage precursors or stem cell-mediated methods for treating severe graft versus host disease (GvHD) in a subject that is non-responsive to at least two previous treatment lines. Background Acute and chronic graft versus host disease (cGvHD) are immunological disorders that are the leading cause of non-recurrent death (NRM) following allogeneic stem cell transplantation. Acute GvHD affects 40% to 60% of patients and targets skin, liver, and gastrointestinal tract. GvHD remains a significant unmet clinical need, especially in patients who have become unresponsive to currently approved therapies. In fact, there is a high level of mortality in these patients. Clearly, there is an unmet therapeutic need in the art for the treatment of GvHD, especially for subjects at high risk of adverse outcome. Disclosure of Invention The inventors surprisingly found that mesenchymal lineage precursors or stem cells are particularly effective in treating GvHD in subjects who have failed at least two previous lines of treatment. Indeed, a significant improvement in survival was observed in GvHD patients administered MSCs as a three-wire treatment. Thus, in a first example, the present disclosure relates to a method of treating graft versus host disease (GvHD) in a human subject in need thereof, the method comprising administering to the subject a composition comprising mesenchymal lineage precursors or stem cells (MLPSC), wherein MLPSC is administered to the subject as a trilinear treatment. In another example, the disclosure relates to a method for treating graft versus host disease (GvHD) in a human subject, the method comprising: i) Selecting a subject having GvHD and having failed the second line treatment; ii) administering to the subject a composition comprising mesenchymal lineage precursors or stem cells (MLPSC), wherein MLPSC is administered to the subject as a trilinear treatment. In one example, a subject treated according to the methods disclosed herein is non-responsive to corticosteroids and second line treatment. In one example, the second line treatment is pontinib. In one example, the second line treatment is a biologic. Exemplary biological agents include alemtuzumab, basiliximab, or tolizumab. In one example, MLPSC in the composition inhibits IL-2Rα expression by ≡60%, wherein inhibition of IL-2Rα expression is determined by obtaining a cell population comprising culture expanded, cryopreserved and thawed MLPSC, co-culturing MLPSC with a cell population comprising T cells in a medium, and determining the level of inhibition of IL-2Rα expression. In one example, the treatment reduces the risk of mortality in the subject. For example, the death may be 6 months non-recurrent death (NRM). In one example, the subject is a pediatric subject. In one example, the subject is 12 years old or older. In another example, the subject has an acute graft versus host disease (aGvHD). In another example, the subject is classified as one or more of: -grade B, grade C or grade D according to IBMTR severity scale; Grade II GvHD according to Glucksberg severity scale; grade III/IV GvHD according to Glucksberg severity scale; Minnesota high risk GvHD. In one example, the subject has chronic GvHD. In one example, the subject has multiple organ involvement. In one example, the subject has Inflammatory Bowel Disease (IBD). In one example, the IBD is crohn's disease or ulcerative colitis. In one example, the IBD is crohn's disease. In one example, crohn's disease occurs in the rectum and/or colon of a subject. In one example, the IBD of the subject is non-responsive to one or more of adalimumab, cetuzumab, vedolizumab, or Wu Sinu mab. In one example, the treatment increases the probability that the subject survives for at least 28 days after initiation of the treatment. In one example, the treatment increases the probability that the subject survives at least 100 days, preferably at least 180 days, after initiation of the treatment. In one example, the treatment increases the probability that the subject survives for at least 100 days after initiation of the treatment. In one example, the probability of survival of the subject is increased relative to a subject who did not receive MLPSC. In one example, the probability of survival of the subject after initiation of treatment is greater than 40%, greater than 50% or preferably greater than 60%. In one example, the probability of survival of the subject after initiation of treatment is greater than 40%. In one example, the probability of survival of the subject after initiation of treatment is greater than 50%. In one example, the probability of survival of the subject after initiation of treatment is greater than 60%. In one example, the probability of survival of a subject after initiation of treatment is between about 30% and about 80%. In one example, the probability of surviv