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Can immunotherapy specifically target acute myeloid leukemic stem cells?

ABSTRACT: Accumulating evidence supports the role of leukemic stem cells (LSCs) in the high relapse rate of acute myeloid leukemia (AML) patients. The clinical relevance of LSCs, which were originally characterized in xenograft models, has recently been confirmed by the finding that stem cell-like gene expression signatures can predict the clinical outcome of AML patients. The targeted elimination of LSCs might hence constitute an efficient therapeutic approach to AML. Here, we review immunotherapeutic strategies that target LSC-associated antigens, including T cell-mediated and monoclonal antibody-based regimens. Attention is given to the issue of antigen specificity because this is relevant to the therapeutic window and determines the superiority of LSC-targeting immunotherapy.

SUBMITTER: Snauwaert S

PROVIDER: S-EPMC3601163 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Can immunotherapy specifically target acute myeloid leukemic stem cells?

Snauwaert Sylvia S Vandekerckhove Bart B Kerre Tessa T

Oncoimmunology 20130201 2

Accumulating evidence supports the role of leukemic stem cells (LSCs) in the high relapse rate of acute myeloid leukemia (AML) patients. The clinical relevance of LSCs, which were originally characterized in xenograft models, has recently been confirmed by the finding that stem cell-like gene expression signatures can predict the clinical outcome of AML patients. The targeted elimination of LSCs might hence constitute an efficient therapeutic approach to AML. Here, we review immunotherapeutic st ...[more]

PMID: 23526057

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Project description:BackgroundLeukemic stem cells (LSCs) are frequently seen as a cause of treatment failure and relapse in patients with acute myeloid leukemia (AML). Thus, successful new therapeutic strategies for the treatment of AML should aim at eradicating LSCs. The identification of targets on the cell surface of LSCs is getting more and more attention. Among these, CD123, also known as the interleukin-3 (IL3)-receptor α chain, has been identified as a potential immunotherapeutic target due to its overexpression on LSCs in AML as well as on AML blasts, rather than normal hematopoietic stem cells.MethodsWe constructed a CD123-targeted fusion protein antiCD3Fv-⊿IL3, with one binding site for T cell antigen receptor (TCRCD3) and the other for CD123, by recombinant gene-engineering technology. Cysteine residues were introduced into the V domains of the antiCD3Fv segment to enhance its stability by locking the two chains of Fv together with disulfide covalent bonds. The stability and cytotoxicity of the two fusion proteins were detected in vitro and in vivo.ResultsBoth fusion proteins were produced and purified from Escherichia coli 16C9 cells with excellent yields in fully active forms. High-binding capability was observed between these two fusion proteins and human IL3R, leading to the specific lysis of CD123-expressing cell lines KG1a; also, mononuclear cells from primary AML patients were inhibited in a colony forming assay in vitro, presumably by redirecting T lymphocytes in vitro. In addition, they displayed an antileukemic activity against KG1a xenografts in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, especially disulfide-stabilized (ds)-antiCD3Fv-⊿IL3 for its improved stability.ConclusionsThese results suggest that both fusion proteins display the antileukemic activity against CD123-expressing cell lines as well as leukemic progenitors in vitro and in vivo, especially ds-antiCD3Fv-⊿IL3. They could be the promising candidates for future immunotherapy of AML.

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Can immunotherapy specifically target acute myeloid leukemic stem cells?

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Can immunotherapy specifically target acute myeloid leukemic stem cells?

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