Hydrogel-based co-delivery of CIK cells and oncolytic adenovirus armed with IL12 and IL15 for cancer immunotherapy
Hydrogel-based co-delivery of CIK cells and oncolytic adenovirus armed with IL12 and IL15 for cancer immunotherapy
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DOI：
10.1016/j.biopha.2022.113110
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发表时间：
2022-05-20
影响因子：
7.5
通讯作者：
Li, Yang
中科院分区：
文献类型：
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作者：
Du, Ya-nan;Wei, Qian;Li, Yang
瘤内注射各种效应细胞与表达抗肿瘤细胞因子的溶瘤腺病毒结合，通过溶瘤和改变肿瘤微环境发挥有效的抗肿瘤免疫作用。然而，这种联合疗法有一定的局限性。当以高浓度使用时，效应细胞和溶瘤病毒可以迅速扩散到周围的非靶组织。由于联合使用的两种疗法都具有免疫原性，并且表现出较短的生物活性，因此需要多次注射以获得足够的治疗指数。为了克服这些缺点，我们封装了明胶基水凝胶，其能够共同递送装备有IL 12和IL 15的溶瘤腺病毒（CRAd-IL 12-IL 15）和CIK细胞，用于在单次瘤内注射后增强和延长两种疗法的抗肿瘤作用。可注射且可生物降解的水凝胶减少了高剂量溶瘤腺病毒和CIK细胞从注射部位分散到肝脏和其他非靶组织。本研究构建了一种新型的溶瘤腺病毒载体CRAd-IL 12-IL 15，该载体能够上调Bcl-2、Cish和Gzmb在肿瘤细胞中的表达水平，从而验证其细胞因子表达和溶瘤能力。CRAd-IL 12-IL 15 + CIK/明胶处理在较长时间段内维持CRAd-IL 12-IL 15和活性CIK细胞的持续释放，减弱针对腺病毒的抗病毒免疫应答。结论：水凝胶介导的CRAd-IL 12-IL 15与CIK细胞的共递送可能是克服其局限性的一种方法。两种治疗均可有效保留在肿瘤组织中，并持续诱导单次给药的强效抗肿瘤免疫应答。
Intratumoral injection of various effector cells combined with oncolytic adenovirus expressing antitumor cytokines exert an effective antitumor immune effect by oncolysis and altering the tumor microenvironment. However, this combination therapy had certain limitations. When used in high concentrations, effector cells and oncolytic viruses can spread rapidly to surrounding non-target tissues. And because both therapies used in combination are immunogenic and exhibit shorter biological activity, multiple injections were required to attain an adequate therapeutic index. To overcome these drawbacks, we encapsulated gelatin-based hydrogel capable of co-deliver oncolytic adenovirus armed with IL12 and IL15 (CRAd-IL12-IL15) and CIK cells for enhancing and prolonging the antitumor effects of both therapies after a single intratumoral injection. The injectable and biodegradable hydrogel reduced the dispersion of high-dose oncolytic adenovirus and CIK cells from the injection site to the liver and other non-target tissues. In this study, a novel oncolytic adenoviral vector CRAd-IL12-IL15 was constructed to verify the cytokine expression and oncolytic ability, which can upregulate the expression levels of Bcl-2, Cish and Gzmb in tumor cells. The CRAd-IL12-IL15 + CIKs/gelatin treatment maintained sustained release of CRAd-IL12-IL15 and active CIK cells over a longer period of time, attenuating the antiviral immune response against adenovirus. In conclusion, the results suggested that hydrogel-mediated co-delivery of CRAd-IL12-IL15 and CIK cells might be a an approach to overcome limitations. Both treatments could be effectively retained in tumor tissue and sustained to induce potent anti-tumor immune responses with a single administration.