title: CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101.
abstract: Sensitivity of chronic lymphocytic leukemia (CLL) cells to anti-CD20 mAbs is low and, therefore, the efficacy of monotherapy with current anti-CD20 mAbs is limited. At present, it is not known whether sensitivity of CLL cells to CD20 mAbs is modulated by microenvironmental stimuli. We have shown previously that in vitro CD40 stimulation of peripheral blood-derived CLL cells results in resistance to cytotoxic drugs. In the present study, we show that, in contrast, CD40 stimulation sensitizes CLL cells to the recently described novel type II anti-CD20 mAb GA101. Cell death occurred without cross-linking of GA101 and involved a lysosome-dependent mechanism. Combining GA101 with various cytotoxic drugs resulted in additive cell death, not only in CD40-stimulated CLL cells, but also in p53-dysfunctional CLL cells. Our findings indicate that GA101 has efficacy against chemoresistant CLL, and provide a rationale for combining cytotoxic drugs with anti-CD20 mAbs.
authors.affiliation: Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands. m.jak@amc.uva.nl
authors.forename: Margot
authors.initials: M
authors.lastname: Jak
authors.forename: Gregor G W
authors.initials: GG
authors.lastname: van Bochove
authors.forename: Eric A
authors.initials: EA
authors.lastname: Reits
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Kallemeijn
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tromp
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Rene A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D019013:CD40 Antigens / Q000378:metabolism*; D016923:Cell Death / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008247:Lysosomes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000069283:Rituximab
chemical_list: D000199:Actins; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D000069283:Rituximab; C543332:obinutuzumab