Abstract 721: Suppression of orthotopic liver cancers by a combinatorial therapy of radiation and adenoviral vectors expressing interleukin 12

Abstract

Abstract 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 (> 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