Naive T-Cell Depleted DLI Following Allo Stem Cell Transplant

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Duke University
Sponsor:
Information provided by (Responsible Party):
Mitchell Horwitz, MD, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01627275
First received: June 21, 2012
Last updated: April 15, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Hematological Malignancies
Biological: Naive T Cell Depleted Donor Lymphocyte Infusion
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Naive T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • 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 3-5/6 HLA matched family donor, 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 96
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)
Arms Assigned Interventions
Experimental: DLI from HLA-identical donor
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
Experimental: DLI from haplo-identical related donor
Donor Lymphocyte Infusion from 3-5/6 HLA matched family member 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

Detailed Description:

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 and HLA-mismatched, 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who have undergone an alemtuzumab or thymoglobulin-containing allogeneic transplant procedure from a 3-5/6 HLA matched family donor, HLA-identical family donor, or an 8/8 HLA-matched unrelated donor.
  • At least 60 days from day of transplantation.
  • Karnofsky performance status 50-100%.
  • Donor myeloid engraftment (from peripheral blood or bone marrow) of at least 40% documented ≤ 60 days from protocol therapy.
  • No active acute GvHD ≥ grade II.
  • Prednisone (or equivalent corticosteroid) dose ≤ 20mg, daily mycophenolate mofetil dose ≤2000mg/d and cyclosporine/tacrolimus at ≤ therapeutic blood trough levels.
  • No change in dosing of immunosuppressive agents 2 weeks before the naïve T-cell depleted donor lymphocyte infusion.
  • A commitment not to electively taper for a minimum of 60 days, the immunosuppressive medications ongoing at time of naïve T-cell depleted donor lymphocyte infusion.
  • No extensive chronic GvHD.
  • Age ≥ 18 years of age.

Exclusion Criteria:

  • Pregnant or lactating women.
  • Patients with other major medical or psychiatric illnesses, which the treating physician feels, could seriously compromise tolerance to this protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01627275

Contacts
Contact: Mitchell E Horwitz, MD (919) 668-1012 horwi001@mc.duke.edu
Contact: Krista Rowe, RN, MSN (919) 684-7115 krista.rowe@duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Mitchell Horwitz, MD    919-668-1012    horwi001@mc.duke.edu   
Contact: Krista Rowe, RN, MSN    (919) 684-7115    krista.rowe@duke.edu   
Principal Investigator: Mitchell Horwitz, MD         
Sponsors and Collaborators
Mitchell Horwitz, MD
Investigators
Principal Investigator: Mitchell Horwitz, MD Duke University
  More Information

No publications provided

Responsible Party: Mitchell Horwitz, MD, Principal Investigator, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT01627275     History of Changes
Other Study ID Numbers: Pro00003975
Study First Received: June 21, 2012
Last Updated: April 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
Naive T Cell Depletion
Donor Lymphocyte Infusion
Allogeneic Hematopoietic Stem Cell Transplant

Additional relevant MeSH terms:
Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases

ClinicalTrials.gov processed this record on July 24, 2014