LYMPHOID NEOPLASIA

toxicity (ADCC), which is largely medi-ated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal anti-body (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimula-tory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb en-hances the antilymphoma activity of ritux-imab by enhancing ADCC. Human NK cells up-regulate CD137 after encounter-ing rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lym-phoma cells. In a syngeneic murine lym-phoma model and in a xenotransplanted human lymphoma model, sequential ad-ministration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilym-phoma activity in vivo. These results sup-port a novel, sequential antibody ap-proach against B-cell malignancies by targeting first the tumor and then the host immune system. (Blood. 2011;117(8): 2423-2432