Image-guided Interventional Combination Liver Cancer Immunotherapy

项目摘要 对于临床应用，基于自然杀伤（NK）细胞的过继转移的关键剩余障碍 免疫疗法（ATI）的缺点是离体扩增的效应NK对靶向的NK细胞的归巢效率不足。 肿瘤组织另一个重大障碍是缺乏完善的非侵入性工具来监测NK 细胞向肿瘤组织的运输。目前，基于NK细胞的ATI（NK-ATI）应答者或无应答者是 通过血清生物标志物或肿瘤大小的变化来识别，这两种变化可能要到数周或数月才发生 治疗开始后。ATI期间NK细胞向肿瘤迁移的系列监测可替代地用作 及时预测纵向反应的重要早期生物标志物，从而提供早期调整， 每个病人的治疗方案 最近，我们的研究表明索拉非尼不仅抑制肿瘤细胞增殖， 促进NK的抗肿瘤活性。因此，索拉非尼的同时给药可能对于 持续的NK活化和细胞毒性。 我们研制了可生物降解的索拉非尼洗脱微球（SEM，直径为492 ± 34 nm; 纳米SEM）输送平台，通过图像引导经导管 IHA交付。我们将开发一种新的影像引导介入联合肝癌免疫治疗 方法包括a）将NK直接经图像引导的经导管IHA输注到靶向血管的血液供应中， 肝肿瘤和B）同时输注纳米SEM以增强索拉非尼B治疗功效（具有最小的 副作用）和增强NK抗肿瘤活性。

PROJECT SUMMARY For clinical application, a critical remaining hurdle for natural killer (NK) cell-based adoptive transfer immunotherapy (ATI) is the inadequate homing efficiency of ex vivo-expanded effector NKs to the targeted tumor tissues. Another significant obstacle is the lack of well-established non-invasive tools for monitoring NK cell trafficking to tumor tissues. Currently, NK cell-based ATI (NK-ATI) responders or non-responders are identified by changes in serum biomarkers or tumor size, both of which may not occur until weeks or months after therapy initiation. Serial monitoring of NK cell migration to tumors during ATI could alternatively serve as an important early biomarker for timely prediction of longitudinal response, thus affording early adjustments to each individual patient’s therapeutic regimen. Recently, our studies have demonstrated that sorafenib not only inhibits tumor cell proliferation, but also promotes antitumor activity of NKs. Therefore, concurrent administration of sorafenib may be critical for sustained NK activation and cytotoxicity. We have developed biodegradable sorafenib-eluting microsphere (SEM, with a diameter of 492 ± 34 nm; nano-SEM) delivery platforms that significantly increase therapeutic efficacy via image-guided transcatheter IHA delivery. We will develop a new image-guided interventional combination liver cancer immunotherapy approach including a) image-guided transcatheter IHA infusion of NKs directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of nano-SEMs to enhance sorafenib therapeutic efficacy (with minimal side effects) and to strengthen NK antitumor activity.