Thursday, 28 February 2013

T-cell infusions may improve Leukaemia survival

Researchers from the Fred Hutchinson Cancer Research Center (FHCRC) recently announced the results of a small clinical trial in relapsed, or high-risk to relapse, leukaemia patients that had previously received an autologous hematopoietic stem cell transplant. The patients were given infusions containing autologous T-cells, which succesfully prolonged the expected survival ratio.

In the trial, the researchers took T-cells from the patients and reprogrammed them in-vitro so that they recognise the Wilm's Tumor Antigen 1. T-cells are a type of white blood cells and play a crucial role in the immune response. The Wilm's Tumor Antigen (WT1) is a protein highly expressed by leukemic cells and is also thought to be one of the reasons why healthy cells transform into leukemic ones.

A total of 11 relapsed or high-risk leukaemia patients, who had previously received a hematopoietic stem cell transplant (HCT) participated in the study. Four of them received WT1 T-Cell infusions. In this group, the T-Cells were grown and cultured in the presence of interleukin-21 (IL-21) which in turn created cells that survived longer and had greater anti-cancer activity. As a result, this group presented with the best results. One of the four patients had actually relapsed prior to the infusions and entered a phase of complete remission for a period of 30 months. Moreover, the IL-21 group:
  • Had no serious adverse effects
  • No graft vs host disease was reported (GVHD)
  • No additional anti-leukemic treatment was required


Image of a platelet, a red blood cell and a T-cell
T lymphocyte (right),  platelet (center),  red blood cell (left)


The findings from the other patients were also promising. These patients received T-Cells that were produced in the abscence of IL-21. One of the patients showed a transient response to his advanced progressive disease and the induction of a prolonged remission was reported to another patient with minimal residual disease. Furthermore, three patients had no relapse, GVHD, or required additional anti-leukemic treatment.

Philip Greenberg, the study's corresponding author, says that this is the first human trial showing that infusions containing WT1 T-cells, can yield "a therapeutic anti-leukemic effect". Aude Chapuis, leading author, said:

"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"

The FHCRC researchers decided to begin the trial because relapse is the main cause of death following an allogeneic HCT in leukemia patients. They were intrigued by the fact that patients who develop GVHD also have a reduced relapse ratio. This indicates that T-cells in engrafted allogeneic hematopoietic stem cells  attack the leukemic cells as well.

This led them to hypothesise that infusions of autologous anti-WT1 T-cells may have the capacity to induce anti-leukemic activity without causing GVHD. Their clinical trial indicates that their theory stands correct.



Reference
Chapuis, A., Ragnarsson, G., Nguyen, H., Chaney, C., Pufnock, J., Schmitt, T., Duerkopp, N., Roberts, I., Pogosov, G., Ho, W., Ochsenreither, S., Wolfl, M., Bar, M., Radich, J., Yee, C., & Greenberg, P. (2013). Transferred WT1-Reactive CD8+ T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients Science Translational Medicine, 5 (174), 174-174 DOI: 10.1126/scitranslmed.3004916

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