Stem cells and specially generated T cells from same donor improve leukemia survival
In a significant advance for harnessing the immune system to treat leukemia, patients with high-risk or relapsed leukemia have been successfully treated with post-stem cell transplantation infusions of large numbers of donor T cells specific for an antileukemic antigen key to prolonging survival. Both the stem cells for transplant and the T cells came from the same matched donors.
A pilot clinical trial used T cells taken from a donor, programmed in the laboratory to recognize Wilm tumor antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote antileukemic activity. The WT1 protein is overexpressed in leukemias and is in part responsible for why the cells have become leukemic.
The best results were achieved when some of the patients received T-cell clones that were exposed to interleukin 21 (IL-21) during the programming and growth processes, based on the hypothesis that such exposure would create cells that could survive longer and produce greater antileukemic activity after transfer. IL-21 promotes T-cell expansion while helping those cells acquire characteristics of central memory T-cells.
“This is the first time patients have received an infusion of WT1-specific T cells, and thus also the first demonstration that such cells can provide a therapeutic antileukemic effect, as has been suggested from earlier vaccine trials that induce less potent responses,” said Philip Greenberg, MD, of Fred Hutchinson Cancer Research Center In Seattle, Washington, and corresponding author. These results were reported in Science Translational Medicine (2013; doi:10.1126/scitranslmed.3004916).
“Ours is also the first report to show that greatly improved T cell in-vivo persistence can be achieved after transfer by modifying the way cells are generated in tissue culture for therapy with inclusion of the cytokine IL-21,” said Aude Chapuis, MD, also of Fred Hutchinson, and the study's lead author.
The findings support expanding efforts to target WT1 and provide insights into what is necessary to establish potent and persistent T-cell responses in patients.
All of the patients, who were treated posttransplant at Seattle Cancer Care Alliance, Fred Hutchinson facility's site for patient care, received adoptively transferred infusions of billions of enhanced CD8 cytotoxic T cell clones. They were considered at high risk of death because they had already relapsed and/or had a poor prognosis due to unfavorable characteristics of their leukemia.
Four of the 11 patients in the trial received infusions of T cells that targeted WT1 and were generated in the presence of IL-21. One had detectable relapsed disease and entered complete remission shortly after the T-cells were infused. All four survived after T-cell therapy without relapse for more than 30 months without suffering graft-vs-host-disease (GVHD) and required no additional antileukemic treatment, according to the study. GVHD is a major complication of stem cell transplantation.
Among the seven patients who received infused T cells generated without the presence of IL-21, two showed direct evidence of antileukemic activity, including one patient with advanced progressive disease who had a temporary response.