Removing Subset of T Cells Reduces Chronic Graft-Versus-Host Disease

Researchers have been looking for ways to reduce graft-versus-hostdisease (GVHD) by changing the T cell composition of the allogenic hematopoietic cell transplants. Eliminating T cells altogether reduces GVHD, but the absence of T cells leads to more opportunistic infections and perhaps to reduced survival. A variety of other partial T-cell depletion tactics have been investigated with the goal of striking the right balance between reducing GVHD while preserving enough T cells to fight off infection, but none have emerged as clear successes.

A research team led by Marie Bleakley, M.D., Ph.D., M.MSc., at the Fred Hutchinson Cancer Center in Seattle, may have arrived solution to the GVHD-T cell dilemma. Alpha-beta T cells include naïve (TN), effector (TE) and memory (TM) subsets, they explained in the findings they reported in the Journal of Clinical Oncology.Experiments in mice showed that the TN resulted in severe GVHD. Those findings, in addition to some preliminary studies in human subjects, led them to try a strategy that involved sifting through the blood stem cells and winnowing out the TN cells from grafts.They zeroed in on patients who received peripheral blood stem-cell grafts because chronic GVHD is especially problematic for those patients and peripheral blood stem-cells are commonly used.

A total of 138 patients with acute leukemia and myelodysplastic syndromereceived the TN-depleted peripheral blood stem-cell grafts in three phase 2 studies. Chronic GVHD occurs in 30% to 60% of patients receiving such grafts that have not been manipulated. Among these patients that received the TN-depleted graft, only 7% experienced chronic GVHD and the cases were mild. Overall survival, relapse-free survival and nonrelapse mortality rates were favorable, an indication that the TN-depleted grafts were not associated with increased risk of relapse or serious infections.

Bleakley and her co-investigators acknowledge that one limitation of this research is the lack of comparison group, other than the historical controls, while also stating that a “that it is unlikely that a randomized trial would disprove that TN-depletion results in much lower incidence of cGVHD (chronic GVHD).” Still, they have started two, randomized phase 2 trials that compare their TN-depleted graft strategy with treatment with “replete” grafts along with tacrolimus and methotrexate.