Naive T-Cell Depleted DLI Following Allo Stem Cell Transplant

Hematological Malignancies Clinical Trial

Official title:

Naive T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01627275
• Other study ID #: Pro00003975
• Status: Completed
• Phase: Phase 1
• First received: June 21, 2012
• Last updated: February 12, 2018
• Start date: June 2012
• Est. completion date: August 3, 2017

Study information

• Verified date: February 2018
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: August 3, 2017
• Est. primary completion date: February 24, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients who have undergone an alemtuzumab or thymoglobulin-containing allogeneic transplant procedure from an 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.

Related Conditions & MeSH terms

• Hematological Malignancies

Intervention

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.

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Mitchell Horwitz, MD

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD of Naive TCD DLI	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.	12 months
Secondary	Immunological Recovery	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.	12 months
Secondary	Overall Incidence of Acute GVHD	To assess the overall incidence of Acute Graft Versus Host Disease	60 Days
Secondary	Overall Incidence of Opportunistic Infections	To assess the overall incidence of opportunistic infections	60 Days
Secondary	Overall Incidence of Chronic GVHD	To assess overall incidence of Chronic Graft Versus Host Disease	12 months