Naive T-Cell Depleted DLI Following Allo Stem Cell Transplant
Allogeneic stem cell transplantation offers the hope of cure for a wide variety of hematologic malignancies. Mature donor T-cells play a critical role in the success or failure of this procedure and a subset of donor T-cells mediate graft-versus-host disease while other subsets provide the foundation for immune recovery. The major challenge in allogeneic stem cell transplantation is determining how to maximally exploit the beneficial effects mediated by T-cells without causing GvHD. This challenge could be overcome by selectively depleting the population of donor T-cells responsible for eliciting the GvHD response. The study hypothesis is depletion of naïve T-cells from the donor lymphocyte inoculum will not cause GVHD while providing T-cells to affect both anti-infection and anti-tumor responses.
Biological: Naive T Cell Depleted Donor Lymphocyte Infusion
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Naive T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation|
- MTD of Naive TCD DLI [ Time Frame: 12 months ] [ Designated as safety issue: No ]To determine the maximum tolerated dose (MTD) of a Naive T cell depleted (TCD) donor lymphocyte infusion (DLI) post alemtuzumab-containing allogeneic transplant procedure from a HLA-identical family donor, or an 8/8 HLA-matched unrelated donor and derive a preliminary assessment of the efficacy of the naive T-cell depleted DLI.
- Immunological Recovery [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Immunological recovery will be assessed by the immune function panel which consists of a standardized panel of T-cell, B-cell, NK-cell, and dendritic cell antibodies, measurement of T-cell function, analysis of B-cell recovery, quantification of Naive T-cell recovery and a T-cell repertoire assay.
- Overall Incidence of Acute GVHD [ Time Frame: 60 Days ] [ Designated as safety issue: Yes ]To assess the overall incidence of Acute Graft Versus Host Disease
- Overall Incidence of Opportunistic Infections [ Time Frame: 60 Days ] [ Designated as safety issue: Yes ]To assess the overall incidence of opportunistic infections
- Overall Incidence of Chronic GVHD [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]To assess overall incidence of Chronic Graft Versus Host Disease
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||June 2018|
|Estimated Primary Completion Date:||June 2016 (Final data collection date for primary outcome measure)|
Experimental: DLI from HLA-identical donor
Naive T Cell Depleted Donor Lymphocyte Infusion from HLA matched family member donor or 8/8 HLA matched unrelated donor.
Biological: Naive T Cell Depleted Donor Lymphocyte Infusion
A single naive T-cell depleted donor lymphocyte infusion will be administered through a peripheral or central venous catheter greater than or equal to 60 days post allogeneic hematopoietic stem cell transplant.
Other Name: CD45RA+ T Cells
Allogeneic stem cell transplantation (SCT) offers the hope of cure for a wide variety of hematologic malignancies. Mature donor T-cells play a critical role in the success or failure of this procedure. A subset of donor T-cells mediates graft-versus-host disease (GvHD). Other subsets provide the foundation for immune recovery. Pan-depletion of mature donor T-cells is an obligate step in haploidentical allogeneic stem cell transplantation. Without this step, the recipient would succumb to lethal acute GVHD. We have had extensive experience with in-vivo donor (and recipient) T-cell depletion using alemtuzumab as part of the bone marrow conditioning regimen. We and others have also used anti-thymocyte globulin for the same purpose. Pan-depletion of T-cells eliminates GvHD but significantly increases the risks of tumor relapse and opportunistic infections. A delayed donor lymphocyte infusion augments immune recovery and the graft versus tumor response, but it comes at the risk of inducing lethal GvHD. This is particularly problematic when the donor and recipient are HLA-discordant. Thus the major challenge in allogeneic stem cell transplantation is determining how to maximally exploit the beneficial effects mediated by T-cells without causing GvHD. This challenge could be overcome by selectively depleting the population of donor T-cells responsible for eliciting the GvHD response. We have been interested in selecting T-cells based on their naïve or memory phenotype to understand the contribution of each of these cells to the pathogenesis of GvHD. Naïve T-cells (CD62L+ or CD45RA+) are T-cells that have not encountered antigens specific for their T-cell receptor. Memory T-cells (CD62L- or CD62L+ or CD45RA-) are T-cells that have previously been exposed to their corresponding cognate antigens. If a donor has not encountered host alloantigens, GvHD-inducing host-reactive T-cells should be contained in the naïve T-cell compartment. In contrast, all the memory phenotype cells should not recognize host alloantigens. If this hypothesis is correct as suggested by several published studies, CD62L- T-cells, which are devoid of naïve T-cells and represent a subset of memory T-cells, should not be able to induce GvHD. The study hypothesis is depletion of naïve T-cells from the donor lymphocyte inoculum will abrogate GVHD while providing immunocompetent memory T-cells to affect an anti-infection and a graft versus tumor response. In this study, we will determine the maximum tolerated dose of a naïve T-cell depleted donor lymphocyte infusion given to patients following HLA-matched allogeneic stem cell transplantation. We will assess the GVHD-inducing potential of this donor lymphocyte infusion and further monitor the impact that this DLI will have on post-transplant immune recovery.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01627275
|Contact: Mitchell E Horwitz, MD||(919) firstname.lastname@example.org|
|Contact: Krista Rowe, RN, MSN||(919) email@example.com|
|United States, North Carolina|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: Mitchell Horwitz, MD 919-668-1012 firstname.lastname@example.org|
|Contact: Krista Rowe, RN, MSN (919) 684-7115 email@example.com|
|Principal Investigator: Mitchell Horwitz, MD|
|Principal Investigator:||Mitchell Horwitz, MD||Duke University|