Wenyin Shi1, Dietmar W Siemann. 1. Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA.
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.
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.
Authors: Alissar El Chediak; Ali Shamseddine; Larry Bodgi; Jean-Pierre Obeid; Fady Geara; Youssef H Zeidan Journal: Med Oncol Date: 2017-08-21 Impact factor: 3.064
Authors: Michael J Gough; Marka R Crittenden; MaryClare Sarff; Puiyi Pang; Steven K Seung; John T Vetto; Hong-Ming Hu; William L Redmond; John Holland; Andrew D Weinberg Journal: J Immunother Date: 2010-10 Impact factor: 4.456
Authors: Jason R Baird; David Friedman; Benjamin Cottam; Thomas W Dubensky; David B Kanne; Shelly Bambina; Keith Bahjat; Marka R Crittenden; Michael J Gough Journal: Cancer Res Date: 2015-11-13 Impact factor: 12.701