Enhancement of radiation therapy by tumor necrosis factor alpha in human colon cancer using a bispecific antibody.
OBJECTIVE
To overcome the systemic side effects of tumor necrosis factor alpha (TNFalpha) injected i.v., we used a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and TNFalpha to target this cytokine in human CEA-expressing colorectal carcinoma treated simultaneously with radiation therapy (RT).
LS174T cell line was used to study the interaction of TNFalpha and radiation on clonogenic cytotoxicity. When TNFalpha (2500 U/mL) was added 12 h before RT, the surviving fraction at 2 Gy was 54% lower than that obtained with irradiation alone (0.23 vs. 0.42, respectively, p = 0.001). At 20%, 50%, or 70% survival, data points were within the envelope of additivity. Concerning in vivo experiments, RT as a single agent slowed tumor progression as compared with the control group (p = 0.027), whereas TNFalpha, BAb, or BAb + TNFalpha had no effect. BAb + TNFalpha + RT combination enhanced the delay for the tumor to reach 2000 mm(3) as compared with RT alone (p = 0.033, for BAb + TNFalpha + RT group vs. RT group).


CONCLUSIONS
These results suggest that TNFalpha in combination with BAb and RT may be beneficial for the treatment of locally advanced colorectal cancer.
Azria
David
D
INSERM EMI0227 Tumor Biology and Antibody Engineering, CNRS GDR2352, Marseille, Montpellier, France.
Dorvillius
Mylène
M
Gourgou
Sophie
S
Martineau
Pierre
P
Robert
Bruno
B
Pugnière
Martine
M
Delard
René
R
Ychou
Marc
M
Dubois
Jean-Bernard
JB
Pèlegrin
André
A
D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D016503:Drug Delivery Systems; D005260:Female; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011867:Radioisotope Teletherapy; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D003037:Cobalt Radioisotopes; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha