A hydrogel matrix prolongs persistence and promotes specific localization of an oncolytic adenovirus in a tumor by restricting nonspecific shedding and an antiviral immune response

Abstract

Currently, intratumoral injection of an oncolytic adenovirus (Ad) is the conventional administration route in clinical trials. Nonetheless, the locally administered Ad disseminates to the surrounding nontarget tissues and has short biological activity due to immunogenicity of Ad, thus necessitating multiple injections to achieve a sufficient therapeutic index. In the present study, a tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-expressing oncolytic Ad (oAd-TRAIL) was encapsulated in a gelatin hydrogel (oAd-TRAIL/gel) to enhance and prolong antitumor efficacy of the virus after a single intratumoral injection. oAd-TRAIL/gel showed greater antitumor efficacy than naked oAd-TRAIL did due to enhanced and prolonged intratumoral accumulation of Ad up to a 20-day period, showing potent induction of apoptosis and inhibition of tumor cell proliferation. Furthermore, the gel system effectively prevented shedding of oncolytic Ad from the injection site to hepatic and other healthy tissues. oAd-TRAIL/gel treatment resulted in a markedly weaker antiviral immune response against Ad relative to naked oAd-TRAIL, further contributing to prolonged persistence of the oncolytic Ad in tumor tissue. Moreover, the hydrogel matrix preserved oAd-TRAIL's ability to induce an antitumor immune response, resulting in higher intratumoral infiltration by CD4(+)/CD8(+) T cells. Taken together, these findings show that single intratumoral administration of the Ad/hydrogel modality may prolong and potentiate the therapeutic efficacy of Ad, modulate the immune reaction in favor of the virotherapy, and enhance intratumoral localization of the virus, ultimately overcoming limitations of oncolytic virotherapy revealed in recent clinical trials.