Novel Nano-immunotherapy for Treatment of Non-small Cell Lung Cancer

非小细胞肺癌(NSCLC)的治疗通常需要多种剧毒药物的组合 药物和放射治疗，是不能治愈的。针对PD-L1/PD-1的免疫检查点抑制物(ICIS)是 导致非小细胞肺癌治疗模式的转变，但5年存活率仍低于20%。 这一快速通道SBIR应用旨在开发一种新的纳米免疫疗法(称为Arac抗原 释放剂和检查点抑制剂)，可以大大提高ICIS的疗效导致治愈 非小细胞肺癌患者的预后。ARAC建立在我们的核心纳米颗粒平台上，能够共同交付 多种治疗药物，在生理盐水(100 Nm)中保持小体积，适合输液和肿瘤 积累。建议的Arac-02将共同传递Polo-like kinase1(PLK1)靶向治疗(Volasertib)， PD-L1抗体和免疫刺激剂CpG。Volasertib 1)选择性地杀死癌细胞，2)调节 免疫抑制肿瘤微环境，以及3)上调癌细胞中PD-L1的表达，提供 利用PD-L1抗体对纳米颗粒进行靶向传递的机会。CpG是一种寡核苷酸， 增强抗原提呈以产生肿瘤特异性T细胞。这些纳米颗粒含有非常高的 PD-L1抗体的表面密度(每个颗粒2000)，促进与PD-L1分子的结合 在癌细胞上，随后内化和PD-L1降解(与30倍游离PD-L1一样有效 抗体)，松开刹车，让T细胞攻击癌症。当给小鼠静脉注射时 在荷肺肿瘤的情况下，共传递伏拉瑟布和PD-L1抗体的纳米颗粒减少了必要的剂量 每种药物的药效提高了5倍。将CpG添加到纳米结构中可触发更强的适应性抗癌 在双侧非小细胞肺癌小鼠模型中进行免疫，导致一些小鼠完全治愈。平台也是 在猴子身上被发现是安全的。 在第一阶段(目标1)，Arac-02将针对负载volasertib、PD-L1抗体和CpG进行优化。材料 将对其大小、靶向特异性、在非小细胞肺癌细胞中的有效性以及在小鼠中的有效性和安全性进行筛选。 在第二阶段，将评估最优的Arac-02的药代动力学、生物分布、疗效和安全性， 单独使用(目标2)和与目前的一线免疫疗法结合使用(目标3)。临床相关性 将利用对ICIS具有抵抗力的原位NSCLC小鼠模型，研究结果将在 人源化小鼠携带两种不同的患者来源的肿瘤，代表患者中的异质性非小细胞肺癌。 免费药物、单药载药纳米粒和一线免疫疗法将被用作基准。 由于其独特的能力刺激适应性免疫反应的各个步骤，Arac-02预计将 提供治疗结果，特别是在与当前的ICIS一起使用以完全阻断时。ARAC-02可以 上调PD-L1水平，从而提高对多种肿瘤类型的疗效，而不考虑基线PD-L1 L1水平。结果将是候选者的选择和IND应用和临床试验的关键数据。

Treatment of non-small cell lung cancer (NSCLC) typically, which requires a combination of many highly toxic drugs and radiation therapy, is not curative. Immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 are causing a paradigm shift in NSCLC treatment, yet the 5-year survival rate remains below 20%. This Fast-Track SBIR application aims to develop a novel nano-immunotherapy (termed ARAC - Antigen Release Agent and Checkpoint Inhibitor) that can greatly improve the efficacy of ICIs leading to curative outcomes for NSCLC patients. ARAC is built upon our core nanoparticle platform capable of co-delivering multiple therapeutic agents, while keeping a small size in saline (100 nm), suitable for infusion and tumor accumulation. The proposed ARAC-02 will co-deliver a polo-like kinase 1 (PLK1)-targeted therapy (volasertib), a PD-L1 antibody, and the immune-stimulant CpG. Volasertib 1) selectively kills cancer cells, 2) modulates the immune-suppressive tumor microenvironment, and 3) upregulates PD-L1 expression in cancer cells, providing opportunity for targeted delivery with PD-L1 antibody on the nanoparticles. CpG is an oligonucleotide that enhances antigen presentation to generate tumor-specific T cells. The nanoparticles contain a very high surface density of PD-L1 antibodies (two thousand per particle), which promotes binding to PD-L1 molecules on cancer cells, followed by internalization and PD-L1 degradation (as effective as 30-fold free PD-L1 antibody), releasing the brakes and allowing T cells to attack the cancer. When given intravenously to mice bearing lung tumors, the nanoparticle co-delivering volasertib and PD-L1 antibody reduced the necessary dose for efficacy of each drug by 5-fold. Adding CpG to the nanoconstructs triggers greater adaptive anti-cancer immunity in a bilateral NSCLC mouse model, leading to complete cures for some mice. The platform was also found to be safe in monkeys. In Phase I (Aim 1), ARAC-02 will be optimized for loading of volasertib, PD-L1 antibody, and CpG. Materials will be screened for size, targeting specificity, efficacy in NSCLC cells, and efficacy and safety in mice. In Phase II, the pharmacokinetic, biodistribution, efficacy, and safety of the optimal ARAC-02 will be assessed, both alone (Aim 2) and in combination with the current first-line immunotherapy (Aim 3). Clinically relevant orthotopic NSCLC mouse models that are resistant to ICIs will be utilized, and findings will be validated in humanized mice bearing two different patient-derived tumors that represent heterogeneous NSCLC in patients. The free drugs, single-drug-loaded nanoparticles, and first-line immunotherapy will be used as benchmarks. Due to its unique ability to stimulate various steps of the adaptive immune response, ARAC-02 is anticipated to provide curative outcomes, especially when used with current ICIs for complete blockade. ARAC-02 can upregulate PD-L1 levels thereby promoting efficacy in a broad range of tumor types regardless of baseline PD- L1 levels. Outcomes will be candidate selection and critical data towards an IND application and clinical trials.