3187 Purpose: To evaluate the in vivo efficacy of a novel proapoptotic mouse monoclonal antibody, TRA-8, which binds to death receptor 5 (TRAIL-R2). TRA-8 acts through a caspase-8 dependent mechanism. The antibody approach to death receptor therapy may be safer than TRAIL-based therapies since TRA-8 does not induce apoptosis in normal tissues. METHODS: The in vivo cytotoxicity of TRA-8 alone and in combination with temozolomide (Tmz) chemotherapy and radiation therapy (RT) was evaluated in D54 glioma xenografts. Athymic nude mice were injected subq with 2x107 cells. 8 treatment groups of 7 mice each were compared: control, TRA-8 alone, RT alone, Tmz alone, RT/TRA-8, RT/Tmz, TRA-8/Tmz, and TRA-8/Tmz/RT (triple therapy). The primary endpoints of these subq experiments were tumor response and regrowth. Two additional intracranial experiments have been performed with 10-11 animals treated per group with TRA-8 alone, Tmz alone, Tmz/RT, triple therapy, or untreated control. RESULTS: In both subq experiments, complete tumor regressions were most common in animals that received triple therapy with the TRA-8/Tmz/RT (12/15 animals) vs. those that did not (4/105 animals), p=<0.001. 3/4 complete regressions that did not receive triple therapy received TRA-8/Tmz. The addition of TRA-8 to either RT or Tmz enhanced tumor growth delay compared to either RT or Tmz alone. TRA-8 alone without Tmz or RT had limited activity in this model. In intracranial experiments, TRA-8 alone had marginal activity. In both studies, the median survivals of triple treated or chemoradiation only treated mice were significantly different from that of control or TRA-8 alone mice. While median survivals of triple-treated mice (107, 219 days) were greater in both studies than those of mice receiving chemoradiation without TRA-8 (75, 166 days), these differences were not statistically significant (p=0.10, p=0.17). CONCLUSIONS: TRA-8 significantly enhances tumor regression and growth delay in vivo in combination with RT and chemotherapy. Intracranial experiments suggest an improvement in survival with the addition of TRA-8 to chemoradiation as compared to chemoradiation alone. Future studies of local administration through CED may improve upon these Results: Supported by ABC2 and Sankyo Co., Ltd. [Table: see text].