Twice Given, Twice Used: Infusion of Stem Cells and Specially Generated T-Cells From Same Donor Improves Leukemia …

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TWICE GIVEN, TWICE USED: INFUSION OF STEM CELLS AND SPECIALLY GENERATED T-CELLS FROM SAME DONOR IMPROVES LEUKEMIA SURVIVAL

Newswise SEATTLE In a significant advance for harnessing the immune system to treat leukemias, researchers at Fred Hutchinson Cancer Research Center for the first time have successfully infused large numbers of donor T-cells specific for a key anti-leukemic antigen to prolong survival in high-risk and relapsed leukemia patients after stem cell transplantation. Both the stem cells for transplant and the T-cells came from the same matched donors.

Reporting results of a pilot clinical trial in the Feb. 27 issue of the journal Science Translational Medicine, researchers describe the use of T-cells that were taken from a donor, programmed in the lab to recognize the Wilms Tumor Antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote anti-leukemic 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 process, based on the hypothesis that such exposure would create cells that could survive longer and produce greater anti-leukemic 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 anti-leukemic effect, as has been suggested from earlier vaccine trials that induce less potent responses, said Philip Greenberg, M.D., corresponding author and head of the Immunology Program at Fred Hutch.

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, M.D., lead author on the study and a research associate in the Fred Hutch Immunology Program.

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, and such second generation studies have recently been initiated at Fred Hutch. All of the patients, who were treated post-transplant at Seattle Cancer Care Alliance, Fred Hutchs 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 and required no additional anti-leukemic treatment, according to the study. GVHD is a major complication of stem cell transplantation.

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Twice Given, Twice Used: Infusion of Stem Cells and Specially Generated T-Cells From Same Donor Improves Leukemia ...