Abstract 723: Liver-detargeted Ad5/48 chimaeric hexon based oncolytic adenovirus targeting TGFβ signaling: A safe and effective approach for the treatment of prostate cancer bone metastases

Abstract

Abstract Background: We have previously shown that systemic delivery of oncolytic Adenovirus 5 (Ad5) expressing soluble transforming growth factorβ receptorII-Fc protein (Ad.sTβRFc) produced anti-tumor responses in a mouse model of prostate cancer bone metastases. However, the majority of the Ad.sTβRFc was taken up by the liver causing hepatic and systemic toxicities. Since Ad5 uptake in the liver is primarily due to its binding with blood factor X (FX), and that Ad48 has much reduced binding with FX, to prevent the adenoviral-induced liver and systemic toxicity, a chimaeric Ad5/48 adenovirus mHAd.sTβRFc was created. Our objective is to examine the safety and efficacy of mHAd.sTβRFc in a mouse model of prostate cancer bone metastases. Methods: Liver toxicity studies. Following intravenous delivery of adenoviruses, H&E staining of the liver tissues were performed to evaluate liver necrosis. Plasma liver alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. Bone metastasis studies. PC3-luc2 cells were injected in left heart ventricle of nude mice. In mice bearing skeletal tumors, vectors were injected via tail vein. Bone metastases were examined by bioluminescence imaging (BLI) and X-ray radiography. Tumor burden was analyzed by H&E staining; osteoclasts were measured by tartarate resistant acid phosphatase staining, plasma calcium levels were determined, and microCT analyses of the bones were performed. Results: Systemic delivery of Ad5 based Ad.sTβRFc showed that a low dose (2.5x1010 viral particles (VPs)/mouse or a high dose (1011 VPs/mouse ) produced significant liver necrosis and a transient increase in ALT and AST levels; the high dose (1011 VPs/mouse) killed all the mice by day 3. On the other hand, intravenous delivery of low or high dose of Ad5/48 chimaeric mHAd.sTβRFc virus did not produce liver damage or increased plasma ALT and AST levels; even the higher doses (up to 2x1011 VPs/mouse) did not cause any animal deaths. There was a much reduced liver uptake of mHAd.sTβRFc compared to Ad.sTβRFc. Intravenous delivery of Ad.sTβRFc and mHAd.sTβRFc (5x1010 viral particles (VPs)/mouse) exhibited a significant inhibition of bone metastases as revealed by BLI and X-ray analyses. The higher doses of mHAd.sTβRFc (2x1011 VPs/mouse or 4x1011 VPs/mouse) were more effective than the lower dose (5x1010 VPs/mouse) of Ad.sTβRFc or mHAd.sTβRFc in inhibiting bone metastases, and produced a significant reduction in the tumor burden, hypercalcemia and osteoclast numbers, and produced normal bone architect as revealed by the microCT scan analyses. Conclusion: Ad5/48 chimaeric hexon based oncolytic adenoviruses produce much reduced liver and systemic toxicity, and can be administered in much larger amounts to produce superior anti-tumor responses, and should be tested in the future clinical trials in prostate cancer patients. Citation Format: Weidong Xu, Zhenwei Zhang, Theresa Guise, Charles B. Brendler, Prem Seth. Liver-detargeted Ad5/48 chimaeric hexon based oncolytic adenovirus targeting TGFβ signaling: A safe and effective approach for the treatment of prostate cancer bone metastases. [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 723. doi:10.1158/1538-7445.AM2014-723