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.

中文翻译：

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通过限制非特异性脱落和抗病毒免疫反应，水凝胶基质可延长持久性并促进溶瘤腺病毒在肿瘤中的特异性定位

当前，瘤内注射溶瘤腺病毒（Ad）是临床试验中的常规给药途径。然而，由于Ad的免疫原性，局部施用的Ad散布到周围的非靶组织，并且具有短的生物学活性，因此需要多次注射以获得足够的治疗指数。在本研究中，将表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）的溶瘤性Ad（oAd-TRAIL）封装在明胶水凝胶（oAd-TRAIL / gel）中，以增强和延长病毒的抗肿瘤功效。一次肿瘤内注射。oAd-TRAIL /凝胶显示出比裸oAd-TRAIL更强的抗肿瘤功效，这是由于Ad的肿瘤内累积和延长时间长达20天所致，显示出有效诱导凋亡和抑制肿瘤细胞增殖的作用。此外，该凝胶系统有效地防止了溶瘤性Ad从注射部位脱落到肝脏和其他健康组织。相对于裸露的oAd-TRAIL，oAd-TRAIL /凝胶处理导致针对Ad的抗病毒免疫反应明显减弱，进一步促进了溶瘤性Ad在肿瘤组织中的持久性。此外，水凝胶基质保留了oAd-TRAIL诱导抗肿瘤免疫反应的能力，从而导致CD4引起较高的肿瘤内浸润 进一步促进了溶瘤性Ad在肿瘤组织中的持久性。此外，水凝胶基质保留了oAd-TRAIL诱导抗肿瘤免疫反应的能力，从而导致CD4引起较高的肿瘤内浸润 进一步促进了溶瘤性Ad在肿瘤组织中的持久性。此外，水凝胶基质保留了oAd-TRAIL诱导抗肿瘤免疫反应的能力，从而导致CD4引起较高的肿瘤内浸润⁺ / CD8 ⁺ T细胞。综上所述，这些发现表明，肿瘤内单次施用Ad /水凝胶可延长和增强Ad的治疗效果，调节免疫反应，有利于病毒疗法，并增强病毒的肿瘤内定位，最终克服溶瘤病毒疗法的局限性在最近的临床试验中发现。