Treatment of Leukemic Blood Samples with Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Is Associated with Reduced Frequencies of Tolerogenic Dendritic Cells and Increased Cytotoxicity Against Autologous Blasts.

Background

Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DCleu), generated from 18 leukemic whole blood (WB) ex vivo using 'Kit-M' (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity against autologous blasts after mixed lymphocyte culture (MLC) with patients' T-cells.

Methods

We studied Kit-M-mediated effects on frequencies of tolerogenic, immunosuppressive DC (DCtol) and correlated findings with ex vivo-achieved antileukemic effects (increased intracellular IFNγ production/degranulation, blast lysis) and patients' clinical characteristics.

Results

We show significantly decreased frequencies of DCtol (and increased frequencies of mature DCleu) without induced blast proliferation in Kit-M treated vs. untreated WB samples. After T-cell-enriched MLC with Kit-M pretreated vs. not pretreated, WB frequencies of regulatory (CD152+ T-cells) were significantly decreased, while 'activated' (IFNγ+, degranulating) non-naive, proliferating, memory, CD154+) T-cells, as well as NK and CIK-cells were (significantly) increased. We found a (significant) positive correlation of achieved improved blast lysis, frequencies of DCleu and 'activated' (IFNγ+/degranulating) T- or NK/CIK cells, and a (significant) negative correlation with frequencies of DCtol and regulatory (CD152+ T-cells). Kit-M treatment of leukemic WB increases DCleu and decreases DCtol, correlating with improved immune reactions/improved cytotoxicity against autologous blasts, and downregulated suppressive T-cells in samples before or after MLC.

Conclusions

These findings demonstrate the potential of Kit-M (using clinically approved drug compositions) to treat AML patients to potentially overcome the immunosuppressive tumor microenvironment, leading to improved antileukemic responses-thereby stabilizing remission of the disease in AML patients.