Abstract 721: Suppression of orthotopic liver cancers by a combinatorial therapy of radiation and adenoviral vectors expressing interleukin 12
Authors: Tao Mi-Hua , Tsao Wen-Shan , Wu Ping-Yi 
Published: May 2015

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Because of difficulty in early diagnosis, only a minority of HCC patients are candidates for resection or transplantation, the traditional curative treatments. Recent development of image-guided radiotherapy and stereotactic radiotherapy offer an alternative therapeutic option for HCC patients with advanced diseases. In addition to eradicate tumor cells via DNA double-strand breaks or induction of apoptosis, radiotherapy also induces immunogenic tumor cell death, releasing a variety of danger-signaling molecules, which may help induce adaptive immune responses against the irradiated local tumors as well as the non-irradiated metastatic tumors. To further increase the therapeutic effect and enhance the antitumor immune responses, we proposed to combine radiation therapy with interleukin 12 (IL-12), a cytokine which has the ability to sensitize suppressive tumor-associated bone marrow-derived stromal cells, enhancing their ability to stimulate CD4+ and CD8+ T cell responses. BALB/c mice were injected at the left liver lobe of 3 x 105 BNL cells, a murine HCC cell line. At day 10, when the tumor volume reaching about 50 mm3, the hepatic tumors were receiving the following treatment: (1) a single dose of radiation of 10 Gy delivering at a mean dose rate of 6.72 Gy/min, (2) a single intratumoral injection of 108 p.f.u. of adenoviral vectors encoding a single-chain murine IL-12 (Ad/IL-12), (3) a combination therapy of 10 Gy radiation and 108 p.f.u. Ad/IL-12, and (4) no treatment. At day 30, mice were sacrificed and the tumor volume was measured by a caliper. The tumors in the control none treated group grew progressively with a mean tumor volume of 2,797 ± 304 mm3. The single treatment of radiation or Ad/IL-12 resulted in objective tumor growth suppression, reducing the mean tumor volume to 367 ± 203 mm3 and 241 ± 204 mm3, respectively, but none of the tumors were regressed after the single agent treatment. In contrast, the combinatorial treatment of radiation and Ad/IL-12 led to a partial (&gt; 50% regression) or complete tumor regression in 80% (8 of 10) of tumors and substantially delayed tumor growth in the tumor-bearing mice. Our preliminary data also showed that the combinatorial treatment of radiation and Ad/IL-12 induced antitumor immune responses and suppressed systemic metastasis. Mechanistic studies of the combinatorial treatment of radiation and Ad/IL-12 are under investigation. Our results suggest that a combinatorial treatment of radiation and IL-12 may represent an alternative therapy for advanced HCC.

Citation Format: Mi-Hua Tao, Wen-Shan Tsao, Ping-Yi Wu. Suppression of orthotopic liver cancers by a combinatorial therapy of radiation and adenoviral vectors expressing interleukin 12. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 721. doi:10.1158/1538-7445.AM2014-721