ARJAN A. VAN DE LOOSDRECHT:  SATURDAY 01 APRIL 2006, 09:00

Leukemia-derived dendritic cell therapy in acute myeloid leukemia

Arjan A. van de Loosdrecht, Ilse Houtenbos, Theresia M. Westers, Gert J. Ossenkoppele
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

Leukemia-derived dendritic cells (DC) enable development of novel immunotherapeutic approaches to eradicate residual leukemic cells. In a large patient cohort (n=154) AML-DC were cultured either in presence of cytokines or calcium ionophore (CI) and IL-4. Cytokine cultures were successful in 58% of patients as evidenced by upregulation of DC markers and increased T cell stimulating capacity. CI-based cultures are feasible in 61%, although this method results in lower viability. Quality of serum-free cultured AML-DC was comparable to serum-enriched cultures indicating feasibility for clinical purposes. AML-DC stimulated autologous T cells were skewed towards a Th1 cytokine profile (IFN g ) and showed cytolytic capacity towards autologous blasts. Additionally, AML-DC show migratory capacity towards lymph node-associated chemokines SDF1 and MIP3 b . Identification of AML populations with DC differentiation capacity is important to select patients eligible for immunisation programs. Presence of Flt-3 internal tandem duplication (ITD) is strongly correlated with decreased DC differentiation capacity in cytokine-based cultures (p<0.001) as well as CI-cultures (p=0.03) suggesting that constitutive activation of tyrosine kinase receptors inhibits differentiation. Regression analysis identified powerful predictors for cytokine-based AML-DC culture outcomes i.e. Flt-3 ITD (p<0.001), CD14 (p<0.001) and TNF a -RI (p<0.001). The model predicts 88% of culture outcomes with high sensitivity (86%) and specificity (92%). In 25% of cases with unsuccessful cytokine-based cultures, CI-based culture method provides an alternative. This percentage increases to 56% if Flt-3 ITD + AML samples are left out. In conclusion, functionally active AML-DC can be generated in most patients with AML. Based on these results, we are including patients for clinical trials.

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