Stimulation of donor t-cells with leukemic blast-loaded dendritic cells for the generation of leukemia-specific immunity in the context of allogeneic stem cell transplantation

Acute myeloid leukemia, a hematopoietic malignant monoclonal disease, is treated initially with chemotherapy and in some cases also by stem cell transplantation (SCT). The relapse rates are high, and long-term disease-free survival occurs in less than half of the AML patients. The curative potential of the allogeneic SCT can be explained by the pre-transplant chemo/radiotherapy in combination with an antitumor effect mediated by specific anti-leukemia donor lymphocytes cells, known as graft versus leukemia effect (GVL). This effect can be induced by the infusion of donor lymphocytes (DLI). Adoptive immunotherapy involving DLI, the current approach in relapsed allogeneic transplant patients, leads in this situation to a complete remission rate of 42%. Unfortunately, DLI is often complicated by graft versus host disease (GVHD), a potential lethal effect mediated also by donor T cells that target host tissues. Since different donor T-cell subsets may be responsible for the GVHD and GVL, it is desirable to generate more specific anti-leukemia cells, which would augment the beneficial GVL effect without causing GVHD. With this objective, we repetitively stimulated resting donor T cells (dTCs) by culturing them with autologous pre-activated dendritic cells (dDCs) loaded with irradiated patient leukemic blasts (p-LBs). The immune reactivity of the stimulated donor-TCs (dSTCs) to the pLBs and other haematopoietic derived patient cells, and a third party leukemic blast (3PLB) were measured by ELISPOT for IFN-g secreting cells and compared with the reaction of non-stimulated donor-TCs (dNSTCs). Three AML patients in relapse or progressive disease and their non-related matched donors were enrolled in the experiment. Although the absolute cell numbers in the cultures usually decreased to the end of the third stimulation, the percentage of dTCs (CD3+), especially the CD8+ subset and the expression of the activation markers CD25 and CD69 increased. dSTCs presented a stronger reaction to the different patient cells and 3P-LBs when compared with the dNSTCs. As dSTCs reacted not only with p-LB and 3P-LB, but also with other patient cells, we concluded that these cells were not strictly leukemia-specific. Since leukemic blasts and non-malignant haematopoietic cells share several antigens, especially the minor histocompatibility antigens, it would be desirable to test the same donor TCs against non-haematopoietic cells.

Author dc:creator

• Gil Alves Portugal, Tatiana

Contributors dc:contributor

• Veelken, Hendrik

• stemcelltransplantation
• Blast
• Leukemia
• dendritic cell
• immunestimulation

Repository record source_url

https://freidok.uni-freiburg.de/data/2039

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:2039