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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1320-1326
NEOPLASIA
Sensitization of B-cell chronic lymphocytic leukemia cells to
recombinant immunotoxin by immunostimulatory phosphorothioate
oligodeoxynucleotides
Thomas Decker,
Susanne Hipp,
Robert J. Kreitman,
Ira Pastan,
Christian Peschel, and
Thomas Licht
From the 3rd Department of Medicine, Technical
University of Munich, Munich, Germany; and the Laboratory of Molecular
Biology, Division of Basic Sciences, National Cancer Institute,
National Institutes of Health, Bethesda, MD.
A recombinant anti-CD25 immunotoxin, LMB-2, has shown clinical
efficacy in hairy cell leukemia and T-cell neoplasms. Its activity in
B-cell chronic lymphocytic leukemia (B-CLL) is inferior but might be
improved if B-CLL cells expressed higher numbers of CD25 binding sites.
It was recently reported that DSP30, a phosphorothioate CpG-oligodeoxynucleotide (CpG-ODN) induces immunogenicity of B-CLL cells by up-regulation of CD25 and other antigens. The present study
investigated the antitumor activity of LMB-2 in the presence of DSP30.
To this end, B-CLL cells from peripheral blood of patients were
isolated immunomagnetically to more than 98% purity. Incubation with
DSP30 for 48 hours augmented CD25 expression in 14 of 15 B-CLL
samples, as assessed by flow cytometry. DSP30 increased LMB-2
cytotoxicity dose dependently whereas a control ODN with no CpG motif
did not. LMB-2 displayed no antitumor cell activity in the absence of
CpG-ODN as determined colorimetrically with an
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. In contrast, B-CLL growth was inhibited in 12 of 13 samples with 50% inhibition concentrations
(IC50) in the range of LMB-2 plasma levels achieved in
clinical studies. Two samples were not evaluable because of spontaneous
B-CLL cell death in the presence of DSP30. Control experiments with an
immunotoxin that does not recognize hematopoietic cells, and an
anti-CD22 immunotoxin, confirmed that sensitization to LMB-2 was
specifically due to up-regulation of CD25. LMB-2 was much less toxic to
normal B and T lymphocytes compared with B-CLL cells. In summary,
immunostimulatory CpG-ODNs efficiently sensitize B-CLL cells to a
recombinant immunotoxin by modulation of its target. This new treatment
strategy deserves further attention.
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