Potentiation of ionising radiation by targeting tumour necrosis factor alpha using a bispecific antibody in human pancreatic cancer

Abstract

The aim of this study was to treat carcinoembryonic antigen (CEA)-expressing pancreatic carcinoma cells with tumour necrosis factor alpha (TNFα) and simultaneous radiation therapy (RT), using a bispecific antibody (BAb) anti-TNFα/anti-CEA. TNFα used alone produced a dose-dependent inhibition of the clonogenic capacity of the cultured cells. Flow cytometry analysis of cell cycle progression confirmed the accumulation of cells in G1 phase after exposure to TNFα. When TNFα was added 12 h before RT, the surviving fraction at 2 Gy was 60% lower than that obtained with irradiation alone (0.29 vs 0.73, respectively, P < 0.00001). In combination treatment, cell cycle analysis demonstrated that TNFα reduced the number of cells in radiation-induced G2 arrest, blocked irreversibly the cells in G1 phase, and showed an additive decrease of the number of cells in S phase. In mice, RT as a single agent slowed tumour progression as compared with the control group (P < 0.00001). BAb + TNFα + RT combination enhanced the delay for the tumour to reach 1500 mm3 as compared with RT alone or with RT + TNFα (P = 0.0011). Median delays were 90, 93, and 142 days for RT alone, RT + TNFα 1 and RT + BAb + TNFα groups, respectively. These results suggest that TNFα in combination with BAb and RT may be beneficial for the treatment of pancreatic cancer in locally advanced or adjuvant settings. © 2003 Cancer Research UK.