Acute myeloid leukemia stem cells and CD33-targeted immunotherapy

Abstract

Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33(-) stem cells as well others arising from, or predominantly involving, committed CD33(+) myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin was the first attempt of such an approach. Emerging clinical data indicate that gemtuzumab ozogamicin is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle evidence for the validity of this strategy. Herein, we review studies on the nature of stem cells in AML, discuss clinical data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success and failure in various AML subsets.

Figure 1

CD33 and CD34 as differentiation antigens. Simplified hypothetical model of stem and progenitor cells in the human hematopoietic system, showing expression patterns of CD33 and CD34.

Figure 2

Proposed models of AML transformation. Three proposed simplified scenarios of step-wise transformation in human AML, leading from a normal cell (green) to a premalignant cell (light red) and, eventually, to a malignant cell (dark red) with clonal expansion: Scenario 1, both the initial transforming event and subsequent mutations leading to clonal expansion occur at the level of multipotent, CD33⁻ precursors; Scenario 2, the initial transforming event occurs at the level of multipotent, CD33⁻ precursors, whereas the collaborating mutational event leading to clonal expansion occurs at the level of CD33⁺ committed myeloid progenitors; and Scenario 3, both initial and subsequent mutations occur at the level of CD33⁺ committed myeloid precursors. Similar models have been proposed by others.

Figure 3

Schematic structure of GO. The humanized IgG₄ anti–CD33 antibody (hP67.6) contains amino acid sequences that are approximately 98.3% of human origin. Lysine residues on hP67.6 are linked to N-acetyl γ-calicheamicin dimethyl hydrazide via a hybrid 4-(4′-acetylphenoxy)butanoic acid linker. The labile hydrazone bond leading to drug release under acidic conditions, presumably within lysosomes, is shaded in green. GO has approximately 50% of the antibody loaded with 4 to 6 mol of the toxic moiety per mole of antibody; the remaining 50% of antibody is unbound. Reproduced with permission from Macmillan Publishers Ltd.