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Graft engineering to improve allogeneic stem cell transplantation

Final Report Summary - GIFT (Graft engineering to improve allogeneic stem cell transplantation)

Allogeneic stem cell transplantation (ASCT) is a curative therapy for numerous malignancies. However, serious complications such as graft-vs-host disease (GVHD) and infection limit the use of this therapy. The objective of this project was to examine whether the novel immunosuppressive agent, FTY720, can be used in donors during stem cell mobilisation to selectively deplete grafts of alloreactive naive T cells (the cells primarily responsible for GVHD) without affecting effector memory T cells or NK cells (cells useful for immunity), thereby creating a graft with low GVHD potential but good antitumor and immune reconstitution potential.

Results

In this study we demonstrated the specific ability of FTY720 to preferentially deplete naive T cells from peripheral blood in contrast to effector memory T cells or NK cells. We also showed for the first time that FTY720 could effectively deplete naive T cells from peripheral blood of donor mice, both under steady state and following G-CSF mobilisation. This level of depletion was found to be sufficient to prevent GVHD following transplant into mismatched recipient mice.

Our study also showed that FTY720 had no significant effect on the killing capacity of NK cells, with NK cells in FTY720-treated mice displaying similar killing capacity as untreated controls. Examination of the effect of FTY720 on human peripheral blood in vitro also revealed no significant negative effects on the functionality of NK cells either in terms of degranulation or cytokine release.

Conclusion

These results demonstrate that FTY720 can be successfully used in donors to selectively deplete naive T cells to prevent GVHD in recipients in an ASCT setting. The ability of FTY720 to specifically deplete naive T cells but not memory T cells or NK cells also demonstrates that it is possible to improve the immunological attribute of the graft. We have shown that the functionality of NK cells is unaffected by FTY720, whilst others have shown that the functionality of memory T cells are also unaffected by this drug. This suggests that maintenance of these cells in the graft can contribute to promoting immunity in the recipient to combat potential infections. Furthermore, the presence of functional NK cells may also contribute to anti-tumor activity provided that the transplant is performed in a KIR mismatched setting.

We are currently performing further experiments to test the functionality of NK cells and memory T cells, present in the graft from FTY720 treated animals, following transplantation to determine whether they can contribute to immunity and anti-tumour activity. We also need to determine the impact of FTY720 on stem cell engraftment to ensure that it has no negative effects on hematopoietic reconstitution. Overall these promising results strongly suggest that FTY720 can be utilised to optimise the immunological attributes of peripheral blood stem cell grafts to avoid GVHD, preserve anti-tumor activity and promote immune reconstitution in ASCT.

The median incidence of GVHD is circa 40 % but can be as high as 80 % depending on risk factors, whilst infection accounts for 30-40 % of treatment-related mortality. Improvements in ASCT protocols over the past 10 years has helped to increase the number of ASCT procedures from 18 000 to over 25 000 annually. Despite these improvements GVHD and infection remain major limiting factors for this procedure.

In the next five years the number of unrelated donor transplants is expected to double and along with it the number of patients with GVHD. This emphasises the need for new protocols to combat GVHD and other treatment related mortalities. The findings from this novel study will help to build on current protocol to further improve the outcome of ASCT and expand its application. Currently severe complications related to ASCT are estimated to increase treatment cost of ASCT.

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