Acute myeloid leukemia (AML) is a rapidly progressing disease that is accompanied by a strong increase in microvessel density in the bone marrow. This observation prompted us to
stain biopsies of AML and
acute lymphoid leukemia (ALL) patients with the clinical-stage human
monoclonal antibodies F8, L19, and F16 directed against markers of
tumor angiogenesis. The analysis revealed that the F8 and F16
antibodies strongly stained 70% of AML and 75% of ALL bone marrow specimens, whereas
chloroma biopsies were stained with all three
antibodies.
Therapy experiments performed in immunocompromised mice bearing human NB4
leukemia with the immunocytokine F8-IL2 [consisting of the
F8 antibody fused to human
interleukin-2 (IL-2)] mediated a strong inhibition of AML progression. This effect was potentiated by the addition of
cytarabine, promoting complete responses in 40% of treated animals. Experiments performed in immunocompetent mice bearing C1498 murine
leukemia revealed long-lasting complete
tumor eradication in all treated mice. The
therapeutic effect of F8-IL2 was mediated by both natural killer cells and CD8(+) T cells, whereas CD4(+) T cells appeared to be dispensable, as determined in immunodepletion experiments. The treatment of an AML patient with disseminated extramedullary AML manifestations with F16-IL2 (consisting of the F16 antibody fused to human IL-2, currently being tested in phase 2 clinical trials in patients with solid
tumors) and low-dose
cytarabine showed significant reduction of AML lesions and underlines the translational potential of vascular
tumor-targeting antibody-
cytokine fusions for the treatment of patients with
leukemia.