Augmented Antitumor Effects of Radiation Therapy by 4-1BB Antibody (BMS-469492) Treatment

Abstract

Background: 4-1BB (CD137) is a member of the tumor necrosis factor receptor superfamily. It interacts with 4-1BB ligand (4-1BBL) and delivers a costimulatory signal for T cell activation. The immune response induced by 4-1BB monoclonal antibodies (mAbs) has been shown to have a marked augmentation of tumor-selective cytolytic T cell activity. Materials and Methods: The antitumor efficacy of agonistic 4-1BB mAbs (BMS-469492, Bristol-Meyer Squibb), used alone or in combination with radiation therapy, was evaluated in murine lung (M109) and breast (EMT6) carcinoma models. Results: Treatment with BMS-469492 led to only a modest growth retardation in M109 tumors (3 days, p>0.05), but a significant growth delay in EMT6 tumors (12.5 days, p<0.05). When BMS-469492 was administered in conjunction with single dose radiation therapy (5, 10 or 15 Gy), enhanced tumor responses were noted only at the highest evaluated radiation dose (15 Gy). In contrast, in the EMT6 model, BMS-469492 treatment resulted in enhanced antitumor effects at all radiation doses. In addition, the response of EMT6 tumors to fractionated radiotherapy also was significantly increased when BMS-469492 was included in the treatment protocol. Conclusion: These results suggest that monoclonal antibodies against 4-1BB may not only be efficacious in cancer immunotherapy, but may also have utility when applied in combination with conventional anticancer treatments, such as radiation therapy.