Downregulation of BCL2 by AT-101 enhances the antileukaemic effect of lenalidomide both by an immune dependant and independent manner

Aisha Masood, Kasyapa Chitta, Aneel Paulus, A. Nazmul H. Khan, Taimur Sher, Noreen Ersing, Kena C. Miller, Deborah Manfredi, Sikander Ailawadhi, Ivan Borrelo, Kelvin P. Lee, Asher A. Chanan-Khan

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Over-expression of anti-apoptotic BCL2 has been reported in chronic lymphocytic leukaemia (CLL), but targeting BCL2 alone did not yield appreciable clinical results. However, it was demonstrated that BCL2 inhibitors enhanced the clinical efficacy of chemo and immunotherapeutics. Lenalidomide, an immunomodulator, is clinically effective in CLL and can enhance the anti-CLL effects of CD20 targeting monoclonal antibody, rituximab. Here, we investigated the mechanism of immune-directed killing of lenalidomide in CLL and evaluated if concurrent targeting of CD20 and BCL2 can enhance this effect. In vitro treatment with lenalidomide enhanced the antibody-mediated cellular cytotoxicity (ADCC) directed by rituximab in autologous leukaemic cells. Furthermore, peripheral blood mononuclear cells obtained from patients after treatment with lenalidomide and rituximab showed increased ADCC in vitro versus control (pre-treatment sample). This effect was further enhanced with pre-treatment of tumour cells with AT-101 (a BH3 mimetic that functions as BCL2 antagonist). Our data suggest that AT-101 in combination with lenalidomide can potentially be an effective therapeutic regimen for CLL.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalBritish journal of haematology
Volume157
Issue number1
DOIs
StatePublished - Apr 1 2012

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Keywords

  • AT-101
  • Antibody-mediated cellular cytotoxicity
  • CD20
  • Chronic lymphocytic leukaemia
  • Lenalidomide

ASJC Scopus subject areas

  • Hematology

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