title: Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts.
abstract: Recombinant human rhApo2L/TRAIL selectively stimulates apoptosis in various cancer cells through its receptors DR4 and DR5, and is currently in clinical trials. Preclinical studies have established antitumor activity of rhApo2L/TRAIL in models of epithelial cancers; however, efficacy in non-Hodgkin lymphoma (NHL) models is not well studied. Of 7 NHL cell lines tested in vitro, rhApo2L/TRAIL stimulated apoptosis in BJAB, Ramos RA1, and DoHH-2 cells. Rituximab, a CD20 antibody used to treat certain types of NHL, augmented rhApo2L/TRAIL-induced caspase activation in Ramos RA1 and DoHH2 but not BJAB or SC-1 cells, through modulation of intrinsic rather than extrinsic apoptosis signaling. In vivo, rhApo2L/TRAIL and rituximab cooperated to attenuate or reverse growth of tumor xenografts of all 4 of these cell lines. Depletion of natural killer (NK) cells or serum complement substantially reduced combined efficacy against Ramos RA1 tumors, suggesting involvement of antibody-dependent cell- and complement-mediated cytotoxicity. Both agents exhibited greater activity against disseminated than subcutaneous BJAB xenografts, and worked together to inhibit or abolish disseminated tumors and increase survival. Moreover, rhApo2L/TRAIL helped circumvent acquired rituximab resistance of a Ramos variant. These findings provide a strong rationale for clinical investigation of rhApo2L/TRAIL in combination with rituximab as a novel strategy for NHL therapy.
authors.affiliation: Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Daniel
authors.forename: Becky
authors.initials: B
authors.lastname: Yang
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.forename: Inessa
authors.initials: I
authors.lastname: Balter
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Cole
authors.forename: Sharon Fong
authors.initials: SF
authors.lastname: Yee
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D008212:Lymphocyte Depletion; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000069283:Rituximab; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D000069283:Rituximab; D003165:Complement System Proteins