Ignite Creation Date:
2024-05-05 @ 4:54 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00342134
Status:
COMPLETED
Last Update Posted:
2017-07-02
First Post:
2006-06-19
Brief Title:
Immunological Mechanisms of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis
Sponsor:
National Institute of Neurological Disorders and Stroke NINDS
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Immunological Mechanisms of Immune Ablation and Autologous Hematopoietic Stem Cell Transplantation in Secondary Progressive Multiple Sclerosis
Status:
COMPLETED
Status Verified Date:
2011-05-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant HSCT and immunoablation by high-dose cyclophosphamide in multiple sclerosis MS
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element We hypothesize and the results of previous studies suggest that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments interferon-beta glatiramer acetate will be enrolled in clinical trials at the collaborating institution NWU-Dr R Burt Dr D Kerr JHU and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells a procedure similar to autologous bone marrow transplantation or high-dose cyclophosphamide treatment without stem cell rescue While the overall treatment-related mortality worldwide is approximately 10 the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which in disease-susceptible individuals may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire To achieve this goal we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS In parallel to identify potential disease-mediating cells that do not recognize these myelin antigens we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire Expanded T cell clones will be tracked during post-transplant follow-up of patients If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses We will combine these studies with a broader unbiased approach that employs microarray technology to identify potential changes in gene expression profiles This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element We hypothesize and the results of previous studies suggest that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments interferon-beta glatiramer acetate will be enrolled in clinical trials at the collaborating institution NWU-Dr R Burt Dr D Kerr JHU and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells a procedure similar to autologous bone marrow transplantation or high-dose cyclophosphamide treatment without stem cell rescue While the overall treatment-related mortality worldwide is approximately 10 the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which in disease-susceptible individuals may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire To achieve this goal we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS In parallel to identify potential disease-mediating cells that do not recognize these myelin antigens we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire Expanded T cell clones will be tracked during post-transplant follow-up of patients If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses We will combine these studies with a broader unbiased approach that employs microarray technology to identify potential changes in gene expression profiles This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment
Detailed Description:
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant HSCT and immunoablation by high-dose cyclophosphamide in multiple sclerosis MS
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element We hypothesize and the results of previous studies suggest that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments interferon-beta glatiramer acetate will be enrolled in clinical trials at the collaborating institution NWU-Dr R Burt Dr D Kerr JHU and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells a procedure similar to autologous bone marrow transplantation or high-dose cyclophosphamide treatment without stem cell rescue While the overall treatment-related mortality worldwide is approximately 10 the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which in disease-susceptible individuals may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire To achieve this goal we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS In parallel to identify potential disease-mediating cells that do not recognize these myelin antigens we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire Expanded T cell clones will be tracked during post-transplant follow-up of patients If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses We will combine these studies with a broader unbiased approach that employs microarray technology to identify potential changes in gene expression profiles This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element We hypothesize and the results of previous studies suggest that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments interferon-beta glatiramer acetate will be enrolled in clinical trials at the collaborating institution NWU-Dr R Burt Dr D Kerr JHU and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells a procedure similar to autologous bone marrow transplantation or high-dose cyclophosphamide treatment without stem cell rescue While the overall treatment-related mortality worldwide is approximately 10 the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which in disease-susceptible individuals may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire To achieve this goal we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS In parallel to identify potential disease-mediating cells that do not recognize these myelin antigens we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire Expanded T cell clones will be tracked during post-transplant follow-up of patients If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses We will combine these studies with a broader unbiased approach that employs microarray technology to identify potential changes in gene expression profiles This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 02-N-N196 | None | None | None |