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

项目摘要 大多数肝细胞癌（HCC）患者接受姑息性肝脏定向治疗; 这些疗法仅提供存活率的适度改善，并且对正常肝组织可能是有毒的。许多 由于潜在的肝功能差，患者不是这些疗法的候选者。 自然杀伤细胞（NK）构成了抵御感染性微生物入侵的第一道防线， 肿瘤细胞NK发挥独立于引发的效应子功能，通过分泌 细胞毒性淋巴因子和破坏肿瘤脉管系统。使用NK的连续转移免疫疗法（ATI） 细胞是治疗造血系统恶性肿瘤和实体瘤的有希望的方法。然而，在这方面， 必须克服关键障碍以在实体瘤中实现有意义的结果。足够数量的NK 细胞必须迁移到肿瘤并浸润肿瘤组织以发挥有效的杀肿瘤功能。有限 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患者通常经历图像引导程序，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液供应中。有针对性的输注提供了显著的 降低全身毒性和递送有效剂量的药物和/或药物洗脱微球。 我们建议通过a）图像引导的免疫治疗从根本上提高NK细胞对HCC的归巢效率。 直接经导管输注到靶向肝肿瘤的血液供应中，和B）同时输注 干扰素-γ（IFN-γ）洗脱微球在计算机断层扫描（CT）成像中可见，以加强 细胞因子梯度驱动NK迁移到肿瘤组织中。 由于效应细胞归巢效率的广泛变化，患者特异性剂量测定和肿瘤预测 在这些过继性转移免疫治疗期间可能难以产生应答。NK细胞的连续体内监测 IFN-γ向肿瘤的迁移和局部递送对于允许早期预测纵向应答是至关重要的 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）。我们提出NK细胞的磁性标记， 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治疗方法， 涉及磁标记NK细胞和IFN-γ的图像引导导管定向递送的方法 洗脱微球用于肝肿瘤。

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.