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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4037-4046.
Prepublished online as a Blood First Edition Paper on August 27, 2007; DOI 10.1182/blood-2007-02-076075.
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Submitted February 27, 2007
Accepted August 17, 2007
Cooperation of the pro-apoptotic receptor agonist
rhApo2L/TRAIL with the CD20 antibody rituximab against
non-Hodgkin's lymphoma xenografts
Dylan Daniel, Becky Yang, David A. Lawrence, Klara Totpal, Inessa Balter, Wyne P. Lee, Alvin Gogineni, Mary J. Cole, Sharon Fong Yee, Sarajane Ross, and Avi Ashkenazi*
Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA, United States
Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, United States
Department of Immunology, Genentech, Inc., South San Francisco, CA, United States
Biomedical Imaging Group, Genentech, Inc., South San Francisco, CA, United States
* Corresponding author; email: aa{at}gene.com.
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's 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 four of these cell lines. Depletion of 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.
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