Image-Guided Transcatheter Delivery of Natural Killer Cell Therapy Augmented with IFN-Gamma Eluting Microspheres

图像引导经导管递送自然杀伤细胞疗法，增强 IFN-γ 洗脱微球

• 批准号: 9766289
• 负责人: Dong-Hyun Kim
• 金额: $ 34.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766289
• 关键词: Address; Adoption; Adoptive Transfer; Alternative Therapies; Cancer Immunology Science; Catheters; Cell Therapy; Cells; Characteristics; Chemotaxis; Contrast Media; Detection; Dose; Effector Cell; Goals; Hematopoietic Neoplasms; Homing; Image; Immunotherapy; In Vitro; Infiltration; Infusion procedures; Interferon Type II; Intervention; Intravenous infusion procedures; Invaded; Kinetics; Label; Liver; Liver neoplasms; Lymphokines; Magnetic Resonance Imaging; Magnetism; Measurement; Methods; Microbe; Microspheres; Modeling; Monitor; Natural Increases; Natural Killer Cells; Necrosis; Outcome; Patients; Pharmaceutical Preparations; Polymers; Primary carcinoma of the liver cells; Procedures; Rattus; Regimen; Relaxation; Solid Neoplasm; Therapeutic; Time; Tissues; Tumor Tissue; Variant; Vascular blood supply; X-Ray Computed Tomography; cancer cell; cell motility; clinical efficacy; cytokine; cytotoxic; dosimetry; image guided; in vivo; in vivo monitoring; individual patient; intrahepatic; liver function; materials science; molecular imaging; nanomedicine; nanoparticle; neoplastic cell; novel therapeutic intervention; oncology; palliative; phantom model; poly(D,L-lactide-co-glycolide); pre-clinical; predicting response; response; systemic toxicity; tumor; tumor vascular supply; uptake

PROJECT SUMMARY Most patients with hepatocellular carcinoma (HCC) are treated with palliative liver-directed therapies; these therapies provide only modest improvements in survival and can be toxic to normal liver tissues. Many patients are not candidates for these therapies due to poor underlying liver function. Natural killer cells (NKs) constitute the first line of defense against invading infectious microbes and neoplastic cells. NKs exert an effector function independent of priming, destroying cancer cells by secreting cytotoxic lymphokines and disrupting the tumor vasculature. Adoptive transfer immunotherapy (ATI) with NK cells is a promising approach for the treatment of both hematopoietic malignancies and solid tumors. However, critical barriers must be overcome to achieve meaningful outcomes in solid tumors. A sufficient number of NK cells must migrate to tumors and infiltrate the tumor tissues to exert potent tumoricidal functions. The limited homing efficiency of NK cells to tumors tissues, following systemic administration, has inhibited clinical efficacy. HCC patients commonly undergo image-guided procedures wherein a catheter is selectively placed to deliver drugs directly into the arterial blood supply of the tumor(s). Targeted infusions afford significant reductions in systemic toxicity and delivery of potent doses of drugs and/or drug-eluting microspheres. We propose radically augmenting the homing efficiency of NK cells to HCC via a) image-guided transcatheter infusion directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of interferon-gamma (IFN-γ) eluting microspheres visible in computed tomography (CT) imaging to strengthen the cytokine gradients that drive NK migration into the tumor tissues. Due to wide variations in effector cell homing efficiency, patient-specific dosimetry and prediction of tumor response can be difficult during these adoptive transfer immunotherapies. Serial in vivo monitoring of NK cell migration to tumors and local delivery of IFN-γ will be critical to permit early prediction of longitudinal response thus affording timely adjustments to each individual patient's therapeutic regimen (additional NK infusion or adoption of alternative therapies as needed). We propose magnetic labeling of NK cells to permit magnetic resonance imaging (MRI) of transcatheter intra-hepatic delivery and local delivered IFN-γ augmented NK cell migration to liver tumors using CT visible microspheres. Through this collaborative project building upon our strengths in materials science, molecular imaging, cancer immunology, nanomedicine and interventional oncology we seek to develop a powerful new therapeutic approach involving image-guided catheter-directed delivery of both magnetically-labeled NK cells and IFN-γ eluting microspheres to liver tumors.

项目概要 大多数肝细胞癌 (HCC) 患者均接受针对肝脏的姑息治疗； 这些疗法仅能适度改善生存，并且可能对正常肝组织产生毒性。许多 由于潜在肝功能较差，患者不适合接受这些治疗。 自然杀伤细胞 (NK) 是抵御感染性微生物入侵的第一道防线 肿瘤细胞。 NK 发挥效应功能，不依赖于启动，通过分泌破坏癌细胞 细胞毒性淋巴因子并破坏肿瘤脉管系统。 NK 过继转移免疫疗法 (ATI) 细胞是治疗造血系统恶性肿瘤和实体瘤的一种有前途的方法。然而， 必须克服关键障碍才能在实体瘤中取得有意义的成果。足够数量的NK 细胞必须迁移到肿瘤并浸润肿瘤组织才能发挥有效的杀肿瘤功能。有限的 全身给药后，NK 细胞向肿瘤组织的归巢效率抑制了临床疗效。 HCC 患者通常会接受图像引导手术，其中选择性地放置导管以 将药物直接输送到肿瘤的动脉血供中。靶向输注可显着 降低全身毒性并递送有效剂量的药物和/或药物洗脱微球。 我们建议通过 a) 图像引导从根本上提高 NK 细胞对 HCC 的归巢效率 经导管直接输注至目标肝脏肿瘤的血液供应中，并且 b) 同时输注 计算机断层扫描 (CT) 成像中可见的干扰素-γ (IFN-γ) 洗脱微球可增强 驱动 NK 迁移到肿瘤组织的细胞因子梯度。 由于效应细胞归巢效率、患者特异性剂量测定和肿瘤预测存在很大差异 在这些过继转移免疫疗法期间，反应可能很困难。 NK 细胞的连续体内监测 向肿瘤的迁移和 IFN-γ 的局部递送对于早期预测纵向反应至关重要 从而及时调整每个患者的治疗方案（额外的 NK 输注或 根据需要采用替代疗法）。我们建议对 NK 细胞进行磁性标记，以允许 经导管肝内递送和局部递送 IFN-γ 的磁共振成像 (MRI) 使用 CT 可见微球增强 NK 细胞向肝脏肿瘤的迁移。 通过这个建立在我们在材料科学、分子成像方面的优势的合作项目， 癌症免疫学、纳米医学和介入肿瘤学，我们寻求开发一种强大的新疗法 涉及图像引导导管定向递送磁性标记 NK 细胞和 IFN-γ 的方法 将微球洗脱到肝肿瘤上。