Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Using RFT5-SMPT-dgA,Specific Anti-IL-2 Receptor Immunotoxin: Reducing GVHD Risk Associated With HLA-Matched, Nonmyeloablative, Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies in Older Adults
Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major
complication after allogeneic stem cell transplantation. Although the most effective way to
prevent GVHD is T cell depletion, this process results in poor immune function leading to
increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a
method of removing GVHD-producing effector cells while retaining a broad T cell repertoire,
including preservation of 3rd party, antiviral and anti-tumor responses would be desirable.
Preclinical studies from our lab have demonstrated that alloreactive T cells can be
selectively removed from the donor lymphocyte pool in vitro with the use of a specific
immunotoxin directed against the interleukin-2 receptor.
To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants
in older patients with hematologic malignancies. Although these patients can be cured with
this approach, they have significant morbidity and mortality from GVHD. At our institution,
nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD
of approximately 50%. Although well tolerated in younger patients, patients over the age of
50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly
related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to
reduce GVHD mortality, while preserving the transplant efficacy.
Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral
blood stem cell allograft from an HLA-identical sibling donor, containing
"selectively-depleted" donor lymphocytes. To obtain such a graft, G-CSF-mobilized peripheral
blood from the donor undergoes a positive CD34 selection followed by a negative T cell
selection using the Nexell Isolex 300i system. This stem cell-rich, T cell-depleted product
will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining
after the positive CD34 selection, is then co-cultured for 72 hours with irradiated
lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24
hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of
1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives
successive infusions of the stem cell product and selected lymphocytes. All patients receive
standard post transplant immunosuppression with cyclosporine for a minimum of 30 days,
followed by dose reduction depending on the degree of donor lymphocyte chimerism.
The primary end point of this study is the incidence and severity of acute GVHD. We will
also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism,
transplant related morbidity and mortality, as well as disease-free and overall survival.
Stopping rules will minimize the risk of untoward or unexpected side effects.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Nonrelapse mortality in the first 100 days of transplant expressed as a percentage of the total subjects. This is different from outcome measure 3 (Cumulative Nonrelapse Mortality), which is cumulative non relapse mortality till December 2011.
100 days after stem cell infusion
A. J Barrett, MD
United States: Federal Government
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