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Warren D. Shlomchik, MD, professor of Medicine and Immunology, director of Hematopoietic Stem Cell Transplantation and Cell Therapies, and scientific director of the Hematopoietic Malignancy Program at UPMC Hillman Cancer Center, has made major contributions in understanding the biology of both GVHD and GVL, and one of his discoveries is now being tested in the clinic with very promising results.
Dr. Shlomchik's lab was the first to publish that naïve T cells (T cells that have never responded to a pathogen or allergen) are more potent than memory T cells at inducing GVHD in mouse models. In close collaboration with colleagues at the Fred Hutchinson Cancer Research Center (supported by the National Institutes of Health [NIH]), Dr. Shlomchik and the FHCRC group developed and published a successful methodology for depleting stem cell grafts of these naïveT cells.4 This work, along with numerous other studies beginning in the early 2000s, culminated in Dr. Shlomchik's first in human clinical trial using allografts depleted of naïve T cells. In this initial phase I/II trial, which ultimately enrolled 41 patients with acute leukemia or advanced myelodysplastic syndrome (MDS), there was only a 9 percent incidence of chronic GVHD. This compares very favorably to an approximate incidence of nearly 50 percent in patients receiving grafts, which include a full complement of T cells. While the incidence of acute GVHD was not reduced, all acute GVHD responded to first line therapies. Dr. Shlomchik and colleagues also showed that T cell memory was effectively transferred from the donor to the recipients as intended. Importantly, overall survival has been at least comparable to transplant studies with similar patients, and because of the low chronic GVHD rate, patients have been more rapidly tapered from their immunosuppression.
Dr. Shlomchik and his collaborators at the Fred Hutchinson Cancer Research Center (Marie Bleakley, MD, principal investigator) are currently conducting a four-arm phase II clinical trial2 of naïve T cell depletion, built upon the phase I trial results. The first trial only enrolled patients with HLA-matched related donors and employed a single high-intensity myeloablative conditioning regimen, which, due to its intensity, excluded patients older than 55. In contrast, the current trial enrolls patients with both HLA-matched related and unrelated donors, and includes both a high-intensity and a lower-intensity conditioning regimen.
Patients aged 18 to 49 will be enrolled into the higher-intensity arms, whereas subjects between 50 and 60, and younger patients ineligible for the higher-intensity regimen, will be enrolled in the lower-intensity conditioning arms. Key objectives will be estimating the rates of chronic and acute GVHD and relapse. Specific immunosuppressive treatments and their duration used to treat GVHD will also be tracked.
This next investigation of naïve T cell depleted grafts will be a phase III randomized clinical trial comparing naïve T cell depletion to standard transplant in pediatric patients with acute leukemia. ChildrenÕs Hospital of Pittsburgh of UPMC will be one of the sites. The anticipation is that the first subject in this trial will be enrolled between May and September 2018. There also are plans for a randomized phase II study to evaluate naïve T cell depletion versus other transplant approaches in adults with leukemia and MDS.
1. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD. ClinicalTrials.gov Identifier: NCT00914940.
2. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD. ClinicalTrials.gov Identifier: NCT02220985.
3. Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of Acute Leukemia Patients Transplanted With Na•ve T Cell-depleted Stem Cell Grafts. J Clin Invest. 2015; 125(7): 2677-2689.
4. Bleakley M, Heimfeld S, Jones LA, Turtle C, Riddell SR, Shlomchik W. Engineering Human Peripheral Blood Stem Cell Grafts That Are Depleted of Naïve T Cells and Retain Functional Pathogen-Specific Memory T Cells. Biol Blood Marrow Transplant. 2014; 20(5): 705-716.