Abstract
BackgroundA549 carrier cells infected with oncolytic adenovirus can induce complete tumor reduction of subcutaneous ovarian tumors but not intraperitoneal disseminated ovarian tumors. This appears to be a result of the insufficient antitumor effect of A549 carrier cells. Therefore, in the present study, we cloned a novel carrier cell with the aim of improving the antitumor effects.MethodsCarrier cells infected with oncolytic adenovirus AdE3‐midkine with a midkine promoter were cloned by limiting dilution. We examined the antitumor effects of these cells on subcutaneous and intraperitoneal OVHM ovarian tumors in a syngeneic mouse model. Biosafety tests were conducted in beagle dogs and rabbits.ResultsWe cloned EHMK‐51‐35 carrier cells with 10‐fold higher antitumor effects compared to A549 carrier cells in vitro. EHMK‐51‐35 carrier cells co‐infected with AdE3‐midkine and Ad‐mGM‐CSF induced a 100% complete tumor reduction in subcutaneous tumors and a 60% reduction of intraperitoneal disseminated tumors. Single‐dose acute toxicity test on beagle dogs with EHMK‐51‐35 carrier cells co‐infected with AdE3‐midkine and Ad‐cGM‐CSF showed no serious side effects. Biologically active adenoviruses were not detected in the blood, saliva, feces, urine or whole organs. In a chronic toxicity test, VX2 tumors in rabbits were injected five times with EHMK‐51‐35 carrier cells infected with AdE3‐midkine and these rabbits showed no serious side effects.ConclusionsSignificant antitumor effects and safety of cloned EHMK‐51‐35 carrier cells were confirmed in intraperitoneal ovarian tumors and toxicity tests, respectively. These findings will be extended to preclinical efficacy studies using dogs and cats, with the aim of conducting human clinical trials on refractory solid tumors.
Highlights
More than 1000 clinical trials of cancer gene therapies have been conducted to date, encouraging clinical results have yet to be obtained.[1]
EHMK‐51‐35 carrier cells infected with AdE3‐midkine or co‐infected with AdE3‐mikine and Ad‐mGM‐CSF were injected three times into subcutaneous OVHM ovarian tumors in syngeneic mice
EHMK‐51‐35 carrier cells infected with AdE3‐midkine or co‐infected with AdE3‐midkine and Ad‐mGM‐CSF induced 80% or 100% of HAMADA ET AL. complete tumor reduction, respectively, which increased the survival rates significantly compared to A549 carrier cells (p < 0.05)
Summary
More than 1000 clinical trials of cancer gene therapies have been conducted to date, encouraging clinical results have yet to be obtained.[1]. Nonpathogenic ECHO‐7 virus without genetic modification (Rigvir) was shown to significantly prolong survival in patients with early‐stage melanoma without any side effects.[3] These viral vectors do not show a significant clinical effect with respect to improving the survival rate of patients with advanced cancers because they result in high titers of neutralizing antibodies that inhibit repetitive viral infections.[4]. We injected the newly developed cloned carrier cells infected with midkine promoter‐driven oncolytic adenovirus into mice, beagle dogs and rabbits aiming to examine antitumor efficacy and biosafety. These efficacy and biosafety tests could comprise a preliminary study for a clinical efficacy trial regarding recurrent canine and feline solid tumors and potentially provide proof‐of‐concept for their use as a pre‐clinical efficacy trial for testing in humans
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