In Vivo Antileukemic Effect and Induction of Leukemia-Derived Dendritic Cells with Immunomodulatory agents in a rat AML model

Abstract

Purpose: Effective therapies for patients with acute myeloid leukemia (AML) remain limited. Here we compare the immune-modulatory potential and anti-leukemic efficacy of the different combinations of responsemodifiers (rat GM-CSF with Prostaglandin E1 (Kit M), Picibanil (Kit I), and Prostaglandin E2 (Kit K)) in a rat leukemia model to convert leukemic myeloid blasts into leukemia-derived dendritic cells (DCleu), re-engaging both innate and adaptive immunity against leukemia and promoting immunological memory in vitro and in vivo, where Kit M was safely used to treat AML patients.

Methods: DC-generation and effect in mixed lymphocyte culture (MLC)-assays upon different treatments were performed. Brown Norway rats with leukemia were treated twice with Kit I, K, or M and compared to untreated controls. Nine days after treatment, blood and spleen samples were analyzed for blasts and immune cell populations.

Results: Kit treatment of leukemic rat-Whole blood (WB) generated DCleu; Kit-pretreated rat-WB with healthy rat T-Lymphocytes in MLC enhanced the antileukemic cytotoxicity. In vivo Kit-treatments were well tolerated. Kit M and Kit I(-high) resulted in a significant reduction of leukemic blasts. Kit I and Kit K displayed similar efficacy in inducing DCleu, memory-like T cells alongside with a reduction in regulatory T cells in all Kits, while Kit M uniquely promoted increased frequencies of memory-like CD8⁺CD62L⁺⁺ T cells indicating induction of immunological memory.

Conclusion: DCleu-inducing in vivo Kits-treatment is safe and induces comparable effects, with Kit M being the most promising candidate for initiating targeted immune responses in AML as previously suggested.