title: Downregulation of BCL2 by AT-101 enhances the antileukaemic effect of lenalidomide both by an immune dependant and independent manner.
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.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Masood
authors.forename: Kasyapa
authors.initials: K
authors.lastname: Chitta
authors.forename: Aneel
authors.initials: A
authors.lastname: Paulus
authors.forename: A Nazmul H
authors.initials: AN
authors.lastname: Khan
authors.forename: Taimur
authors.initials: T
authors.lastname: Sher
authors.forename: Noreen
authors.initials: N
authors.lastname: Ersing
authors.forename: Kena C
authors.initials: KC
authors.lastname: Miller
authors.forename: Deborah
authors.initials: D
authors.lastname: Manfredi
authors.forename: Sikander
authors.initials: S
authors.lastname: Ailawadhi
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrelo
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
authors.forename: Asher
authors.initials: A
authors.lastname: Chanan-Khan
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000276:immunology; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology; D000069283:Rituximab; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000972:Antineoplastic Agents, Phytogenic; D007155:Immunologic Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide; D006072:Gossypol; C028178:gossypol acetic acid