Local Tumoral Delivered Immune Checkpoint Blockades Immunotherapy and Radioembolization Combination Therapy

项目摘要 系统性单一或联合免疫检查点阻断（ICB）免疫疗法已成为一种成熟的治疗方法。 治疗范例然而，严重的自身免疫副作用的风险已被证明与非特异性 细胞毒性T细胞扩增。大量的研究已经调查了如何最好地利用抗肿瘤 联合免疫疗法的潜力以及如何将免疫疗法导向肿瘤。肝细胞 肝癌（HCC）是世界上第五大常见恶性肿瘤，也是世界上第四大癌症死亡原因。 美方切除和移植是HCC唯一可能治愈的治疗方法，但只有10-15%的患者接受了手术。 患者是候选人。最近的临床试验证明了ICB抗体对程序性 细胞死亡1（PD-1）或其配体PD-L1用于治疗HCC。然而，强免疫抑制 微环境和免疫检查点分子在HCC肿瘤内的低表达导致HCC肿瘤内的免疫缺陷。 HCC对免疫疗法的抵抗;因此，ICB免疫疗法的疗效可能不足以引起 持久的临床效益。90 Y-放射性栓塞（90 Y-RE）可以精确地向HCC提供高剂量的放射， 保护健康组织，避免副作用。90 Y-RE是ICB的理想补充 给予90 Y-RE免疫治疗诱导免疫原性细胞死亡。最近临床试验已经开始 评估全身性ICB免疫治疗联合90 Y-RE，希望提高整体 治疗效果然而，导致联合ICB疗效受损的一个限制是， 免疫疗法是在全身施用后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变，以避免全身性非特异性激活肿瘤细胞。 免疫系统我们提出了抗PD-L1（aPD-L1）负载Au的导管定向动脉内（IA）输注 超纳米结构（AuSN）与90 Y-RE的组合。导管引导的局部输注aPD-L1， 高表面积和活性氧物种响应可降解的AuSN将增加 针对靶向HCC的免疫疗法允许免疫系统的放射增强激活， 上级治疗结果。我们提出的肿瘤IA输注的抗PD-L1负载的AuSN将允许有效的 和免疫刺激性aPD-L1的靶向递送，以允许增加剂量和提高安全性， profile. AuSN携带者的局部ICB递送将提供显著增加局部免疫的潜力。 90 Y-RE的刺激功效。我们的CT可见AuSN和横断面CT和MR图像引导应 还允许我们监测/跟踪/量化aPD-L1-AuSN向靶向肿瘤组织的递送。应当 允许早期预测引发的反应，以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。 联合aPD-L1免疫疗法和90 Y-RE治疗HCC。

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.