Local Tumoral Delivered Immune Checkpoint Blockades Immunotherapy and Radioembolization Combination Therapy

项目总结 系统性单一或联合免疫检查点阻断(ICB)免疫疗法已被确立 治疗范例。然而，已证实存在严重自身免疫副作用的风险。 细胞毒性T细胞扩增。大量研究已经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 癌症是世界第五大常见恶性肿瘤，也是#年导致癌症死亡的第四大原因。 美国。切除和移植是唯一有可能治愈肝癌的方法，但只有10%-15%的人 患者是候选对象。最近的临床试验证实了ICB抗体对程序性疾病的潜在作用 细胞死亡1(PD-1)或其配体PD-L1用于治疗肝癌。然而，强烈的免疫抑制作用 肝细胞癌肿瘤内微环境和免疫检查点分子的低表达导致 肝细胞癌对免疫治疗的抵抗；因此，ICB免疫治疗的疗效可能不足以诱导 持久的临床益处。90Y-放射栓塞术(90Y-RE)可以精确地将高剂量的辐射输送到肝癌， 保护健康组织，避免副作用。90Y-RE应是ICB的理想补充 免疫治疗给予90Y-RE诱导免疫原性细胞死亡。最近，临床试验已经开始。 评价全身ICB免疫疗法与90Y-RE的联合应用，以期全面提高 治疗效果。然而，导致联合ICB疗效下降的一个限制是 免疫治疗是指全身给药后ICBS与正常组织的非靶点结合。理想的情况是这些 ICBS应该选择性地输送到肿瘤病变处，以避免全身非特异性激活 免疫系统。我们提出了经导管动脉内注入抗PD-L1(apd-L1)载金 超纳米结构(AuSN)与90Y-RE相结合。经导管局部输注apd-L1 高比表面积和活性氧物种响应性可降解AuSN将增强本地化 靶向肝癌的免疫治疗允许放射增强免疫系统的激活 卓越的治疗效果。我们建议的肿瘤免疫注射抗PD-L1负载的AuSN将允许有效的 和靶向递送免疫刺激雪崩毒素-L1，以增加剂量和改善安全性 侧写。AuSN携带者的本地ICB传递将提供显著提高当地免疫力的潜力- ~(90)Y-RE的刺激效应。我们的CT可见AuSN和横断面CT和MR图像引导应该 此外，我们还可以监控/跟踪/量化apd-L1-AuSN对靶向肿瘤组织的输送。它应该是 允许及早预测引起的反应，以及时调整个别治疗方案。 通过一个合作项目，我们寻求开发一种针对肿瘤局部的强大的新方法 Apd-L1免疫联合90Y-RE治疗肝细胞癌

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.