Local Tumoral Delivered Immune Checkpoint Blockades Immunotherapy and Radioembolization Combination Therapy

局部肿瘤传递的免疫检查点阻断免疫疗法和放射栓塞联合疗法

基本信息

批准号：
10718531
负责人：
Dong-Hyun Kim
金额：
$ 35.72万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718531
关键词：
90Y Aftercare Antibodies Area Autoimmune Binding Cancer Etiology Catheters Cell Death Cell Maturation Cessation of life Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Complement Cytotoxic T-Lymphocytes Dendritic Cells Dose Excision Flow Cytometry Gold Immune Immune response Immune system Immunohistochemistry Immunologic Stimulation Immunologics Immunotherapy In Vitro Individual Infusion procedures Intervention Intra-Arterial Infusions Lead Lesion Ligands Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of liver Measurement Microspheres Monitor Nanoimmunotherapy Nanostructures Normal tissue morphology Oncology PD-L1 blockade Patients Primary carcinoma of the liver cells Procedures Protocols documentation Radiation Radiation Dose Unit Radiation therapy Radio Radioembolization Radiology Specialty Reactive Oxygen Species Research Resistance Risk Rodent Model Safety Surface Therapeutic Therapeutic Effect Tissues Transplantation Treatment Efficacy Treatment Protocols Treatment outcome Tumor Tissue Tumor-infiltrating immune cells Up-Regulation X-Ray Computed Tomography anti-PD-L1 anti-PD-L1 therapy anti-cancer anti-cancer therapeutic attenuation cancer cell curative treatments dosage follow-up image guided imaging properties immune activation immune checkpoint immune checkpoint blockade immunogenic cell death improved liver cancer model novel strategies programmed cell death protein 1 response side effect targeted delivery therapy outcome tumor

项目摘要

PROJECT SUMMARY Systemic mono- or combination- immune checkpoint blockade (ICB) immunotherapy has been an established therapeutic paradigm. However, a risk of serious autoimmune side effect has been evidenced with non-specific cytotoxic T cell expansion. Substantial research has investigated into how best to harness the antitumor potential of combination immunotherapies and how to direct immunotherapies at the tumor. Hepatocellular carcinoma (HCC) is the 5th most common malignancy in the world and the 4th leading cause of cancer death in the US. Resection and transplantation are the sole potentially curative treatments for HCC, but only 10-15% of patients are candidates. Recent clinical trials demonstrate the potential of ICB antibodies against programmed cell death 1 (PD-1) or its ligand PD-L1 for the treatment of HCC. However, the strong immune suppressive microenvironment and low expression of immune checkpoint molecules within the HCC tumor lead to a resistance to immunotherapy in HCC; thus, the efficacy of ICB immunotherapy may not be sufficient to elicit durable clinical benefits. 90Y-radioembolization (90Y-RE) can precisely deliver high doses of radiation to HCC, protecting healthy tissues and avoiding side effects. 90Y-RE should be an ideal complement to ICB immunotherapy given that 90Y-RE induces immunogenic cell death. Recently clinical trials have been initiated to evaluate systemic ICB immunotherapy in combination with 90Y-RE in the hope of enhancing overall therapeutic effects. However, one limitation that accounts for the compromised efficacy of combined ICB immunotherapy is off-target binding of the ICBs to normal tissues upon systemic administration. Ideally these ICBs should be delivered selectively to the tumor lesion to avoid systemic non-specific activation of the immune system. We propose catheter-directed intra-arterial (IA) infusion of anti-PD-L1 (aPD-L1) loaded Au supra-nanostructures (AuSN) in a combination with 90Y-RE. Catheter directed local infusion of aPD-L1 with high surface area and reactive oxygen species responsive degradable AuSN will augment the localization of immunotherapy to the targeted HCC permitting radiation-enhanced activation of the immune system for superior therapeutic outcomes. Our proposed tumoral IA infused anti-PD-L1 loaded AuSN will permit efficient and targeted delivery of immunostimulatory aPD-L1 to allow an increase in the dosage and improved safety profile. The local ICB delivery of AuSN carriers will offer the potential to significantly increase the local immune- stimulating efficacy of 90Y-RE. Our CT visible AuSN and cross-sectional CT and MR image guidance should also permit us to monitor/track/quantify the delivery of aPD-L1-AuSN to the targeted tumor tissues. It should allow early prediction of elicited responses to prompt timely adjustments to individual treatment regimens. Through a collaborative project, we seek to develop a powerful new approach for tumor directed local combinational aPD-L1 immunotherapy and 90Y-RE for the treatment of HCC.

项目概要全身性单一或组合免疫检查点阻断（ICB）免疫疗法已被确立治疗范式。然而，非特异性治疗已证明存在严重自身免疫副作用的风险。细胞毒性 T 细胞扩增。大量研究调查了如何最好地利用抗肿瘤药物联合免疫疗法的潜力以及如何针对肿瘤进行免疫疗法。肝细胞肝癌（HCC）是世界上第五大最常见的恶性肿瘤，也是癌症死亡的第四大原因美国。切除和移植是 HCC 唯一可能治愈的治疗方法，但仅占 10-15% 患者是候选人。最近的临床试验证明了 ICB 抗体对抗编程的潜力细胞死亡 1 (PD-1) 或其配体 PD-L1 用于治疗 HCC。然而，较强的免疫抑制作用 HCC 肿瘤内的微环境和免疫检查点分子的低表达导致 HCC 对免疫治疗的耐药性；因此，ICB免疫疗法的功效可能不足以引起持久的临床效益。 90Y-放射栓塞（90Y-RE）可以精确地将高剂量的辐射传递到HCC，保护健康组织并避免副作用。 90Y-RE应该是ICB的理想补充鉴于 90Y-RE 会诱导免疫原性细胞死亡，因此进行免疫疗法。近期已启动临床试验评估全身 ICB 免疫疗法与 90Y-RE 的联合治疗，以期增强整体效果治疗效果。然而，一个限制因素导致了联合 ICB 的功效受损免疫疗法是全身给药后 ICB 与正常组织的脱靶结合。理想情况下这些 ICB 应选择性地递送至肿瘤病灶，以避免全身非特异性激活免疫系统。我们建议通过导管引导动脉内 (IA) 输注抗 PD-L1 (aPD-L1) 负载的 Au 超纳米结构 (AuSN) 与 90Y-RE 的组合。导管引导局部输注 aPD-L1 高表面积和活性氧响应的可降解 AuSN 将增强针对靶向 HCC 的免疫疗法允许辐射增强免疫系统的激活优越的治疗效果。我们提出的肿瘤 IA 注入抗 PD-L1 负载的 AuSN 将允许有效免疫刺激性 aPD-L1 的靶向递送，以增加剂量并提高安全性轮廓。 AuSN 载体的局部 ICB 递送将有可能显着提高局部免疫 90Y-RE 的刺激功效。我们的 CT 可见 AuSN 以及横截面 CT 和 MR 图像引导应该还允许我们监测/跟踪/量化 aPD-L1-AuSN 向目标肿瘤组织的递送。它应该允许及早预测引发的反应，以提示及时调整个体治疗方案。通过一个合作项目，我们寻求开发一种强大的新方法，用于肿瘤定向局部治疗 aPD-L1 免疫疗法和 90Y-RE 联合治疗 HCC。