An investigation of adverse effects caused by the injection of high-dose TNFα-expressing adenovirus vector into established murine melanoma

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Abstract
We previously reported that RGD fiber-mutant adenovirus vector carrying human TNFα cDNA (AdRGD-TNFα) could more effectively induce mouse B16 BL6 melanoma regression than conventional Ad-TNFα on intratumoral injection at less than 109 vector particles (VP). Although mice treated with either Ad type at 1010 VP showed remarkable tumor regression due to hemolytic necrosis, severe adverse effects including extreme reduction in body weight were also induced by Ad treatment. Here, we attempted to elucidate the cause of the adverse effects to optimize the application of AdRGD-TNFα. More than 99% of systemically administered Ad accumulated in the liver, and the rate of Ad leakage into systemic circulation from the B16 BL6 tumors injected with AdRGD or conventional Ad at 1010 VP was about 1% of the administered VP. Although the leaked Ad did not directly induce hepatotoxicity or body weight reduction, excessive TNFα produced in the tumors leaked into the blood at high concentrations and caused systemic inflammation, tissue denaturation, and body weight reduction in mice injected intratumorally with AdRGD-TNFα or Ad-TNFα at 1010 VP. Our results demonstrated that an exact AdRGD-TNFα dosage must be determined to prevent TNFα leakage from tumors into systemic circulation, thereby enabling safe application of AdRGD-TNFα to clinical melanoma gene therapy in the future.