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: 10176483
• 负责人: Dong-Hyun Kim
• 金额: $ 34.01万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176483
• 关键词: Address; Adoption; Adoptive Transfer; Alternative Therapies; Catheters; 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; NK cell therapy; Natural Increases; Natural Killer Cells; Necrosis; Oncology; 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; palliative; phantom model; poly(D,L-lactide-co-glycolide); pre-clinical; predicting response; response; systemic toxicity; tumor; tumor immunology; 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.

项目总结 大多数肝细胞癌(肝细胞癌)患者接受姑息性肝导向治疗； 这些疗法只能适度提高存活率，而且可能会对正常肝组织产生毒性。许多 由于潜在的肝功能不佳，患者不适合接受这些治疗。 自然杀伤细胞(NKs)是抵御入侵的传染病微生物的第一道防线 肿瘤细胞。NKs发挥一种不依赖于启动的效应作用，通过分泌破坏癌细胞 细胞毒性淋巴因子和扰乱肿瘤血管。NK细胞的过继转移免疫治疗(ATI) 细胞是治疗血液系统恶性肿瘤和实体瘤的一种很有前途的方法。然而， 必须克服关键障碍，才能在实体肿瘤中取得有意义的结果。足够数量的NK 细胞必须迁移到肿瘤中，并渗透到肿瘤组织中，才能发挥强大的杀瘤作用。有限的 全身给药后，NK细胞对肿瘤组织的归巢效率抑制了临床疗效。 肝细胞癌患者通常接受影像引导的手术，其中选择性地将导管放置到 将药物直接输送到肿瘤的动脉供血中(S)。有针对性的输液提供了显著的 减少全身毒性和大剂量药物和/或药物洗脱微球的输送。 我们建议通过图像引导从根本上提高NK细胞对肝癌的归巢效率。 直接经导管输注供血肝肿瘤(S)与b)同时输注 干扰素-γ洗脱在CT成像中可见的微球，以增强 推动NK向肿瘤组织迁移的细胞因子梯度。 由于效应细胞归巢效率、患者特定剂量测定和肿瘤预测的巨大差异 在这些过继转移免疫疗法中，反应可能很困难。自然杀伤细胞的连续活体监测 转移到肿瘤和局部注射干扰素-γ将是早期预测纵向应答的关键 从而及时调整每个患者的治疗方案(额外的NK输注或 视需要采用替代疗法)。我们建议对NK细胞进行磁性标记，以允许 经导管肝内给药和局部给药干扰素-γ的磁共振成像 利用CT可见微球增强NK细胞向肝脏肿瘤的迁移。 通过这个合作项目，我们在材料科学、分子成像、 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 影像引导导管引导磁性标记NK细胞和干扰素-γ联合输送的方法 为肝脏肿瘤洗脱的微球。

项目成果

Enhanced natural killer cell anti-tumor activity with nanoparticles mediated ferroptosis and potential therapeutic application in prostate cancer.

• DOI: 10.1186/s12951-022-01635-y
• 发表时间: 2022-09-29
• 期刊: JOURNAL OF NANOBIOTECHNOLOGY
• 影响因子: 10.2
• 作者: Kim, Kwang-Soo;Choi, Bongseo;Choi, Hyunjun;Ko, Min Jun;Kim, Dong-Hwan;Kim, Dong-Hyun
• 通讯作者: Kim, Dong-Hyun