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Radiocurability by targeting tumor necrosis factor-alpha using a bispecific antibody in carcinoembryonic antigen transgenic mice.

Larbouret C, Robert B, Linard C, Teulon I, Gourgou S, Bibeau F, Martineau P, Santoro L, Pouget JP, Pelegrin A, Azria D

INSERM, Centre de Recherche en Cancérologie de Montpellier, Université de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France.

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) enhances radiotherapy (RT) killing of tumor cells in vitro and in vivo. To overcome systemic side effects, we used a bispecific antibody (BsAb) directed against carcinoembryonic antigen (CEA) and TNF-alpha to target this cytokine in a CEA-expressing colon carcinoma. We report the evaluation of this strategy in immunocompetent CEA-transgenic mice. METHODS AND MATERIALS: The murine CEA-transfected colon carcinoma MC-38 was used for all experiments. In vitro, clonogenic assays were performed after RT alone, TNF-alpha alone, and RT plus TNF-alpha. In vivo, the mice were randomly assigned to treatment groups: control, TNF-alpha, BsAb, BsAb plus TNF-alpha, RT, RT plus TNF-alpha, and RT plus BsAb plus TNF-alpha. Measurements of endogenous TNF-alpha mRNA levels and evaluation of necrosis (histologic evaluation) were assessed per treatment group. RESULTS: In vitro, combined RT plus TNF-alpha resulted in a significant decrease in the survival fraction at 2 Gy compared with RT alone (p < 0.00001). In vivo, we observed a complete response in 5 (50%) of 10, 2 (20%) of 10, 2 (18.2%) of 11, and 0 (0%) of 12 treated mice in the RT plus BsAb plus TNF-alpha, RT plus TNF-alpha, RT alone, and control groups, respectively. This difference was statistically significant when TNF-alpha was targeted with the BsAb (p = 0.03). The addition of exogenous TNF-alpha to RT significantly increased the endogenous TNF-alpha mRNA level, particularly when TNF-alpha was targeted with BsAb (p < 0.01). The percentages of necrotic area were significantly augmented in the RT plus BsAb plus TNF-alpha group. CONCLUSION: These results suggest that targeting TNF-alpha with the BsAb provokes RT curability in a CEA-expressing digestive tumor syngenic model and could be considered as a solid rationale for clinical trials.

Published 30 October 2007 in Int J Radiat Oncol Biol Phys, 69(4): 1231-7.
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