Potentiation of ionising radiation by targeting tumour necrosis factor alpha using a bispecific antibody in human pancreatic cancer.
The aim of this study was to treat carcinoembryonic antigen (CEA)-expressing pancreatic carcinoma cells with tumour necrosis factor alpha (TNFalpha) and simultaneous radiation therapy (RT), using a bispecific antibody (BAb) anti-TNFalpha/anti-CEA. TNFalpha 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 G(1) phase after exposure to TNFalpha. When TNFalpha 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 TNFalpha reduced the number of cells in radiation-induced G(2) arrest, blocked irreversibly the cells in G(1) 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+TNFalpha+RT combination enhanced the delay for the tumour to reach 1500 mm(3) as compared with RT alone or with RT+TNFalpha (P=0.0011). Median delays were 90, 93, and 142 days for RT alone, RT+TNFalpha, and RT+BAb+TNFalpha groups, respectively. These results suggest that TNFalpha in combination with BAb and RT may be beneficial for the treatment of pancreatic cancer in locally advanced or adjuvant settings.
Azria
D
D
Tumour Immunotargeting and Antibody Engineering, INSERM, EMI 0227, 34298 Montpellier, France.
Larbouret
C
C
Garambois
V
V
Kramar
A
A
Martineau
P
P
Robert
B
B
Aillères
N
N
Ychou
M
M
Dubois
J B
JB
Pèlegrin
A
A
D000230:Adenocarcinoma / Q000473:pathology*; D018033:Antibodies, Bispecific / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D016196:S Phase; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D014409:Tumor Necrosis Factor-alpha