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

治疗非小细胞肺癌的新型纳米免疫疗法

• 批准号: 10395367
• 负责人: Worapol Ngamcherdtrakul
• 金额: $ 37.8万
• 依托单位: PDX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395367
• 关键词: Accounting; Antigen Presentation; Antigens; Antineoplastic Agents; Benchmarking; Bilateral; Binding; Biodistribution; Biological Markers; Body Weight; Buffers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cancer Survivor; Cancer cell line; Cell Death; Cells; Cessation of life; Clinical Trials; Data; Dose; Dose-Limiting; Drug Combinations; Drug Kinetics; Feedback; Flow Cytometry; Growth; Health; Hematology; Heterogeneity; Histocompatibility Antigens Class II; Histology; Human; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunocompetent; Immunohistochemistry; Immunotherapy; Infiltration; Infusion procedures; Intravenous; Lead; Legal patent; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Minority; Mitotic; Modeling; Monitor; Monkeys; Mus; Nanoimmunotherapy; Non-Small-Cell Lung Carcinoma; Normal Cell; Oligonucleotides; Outcome; PD-1/PD-L1; PLK1 gene; Particle Size; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phosphotransferases; Positioning Attribute; Proteins; Quality of life; Radiation therapy; Regimen; Renal function; Resistance; STAT3 gene; Safety; Saline; Scheme; Small Business Innovation Research Grant; Specificity; Surface; Survival Rate; T-Lymphocyte; Technology; Testing; Therapeutic Agents; Toxic effect; Treatment Protocols; Tumor Escape; Tumor Immunity; Tumor-Derived; Woman; adaptive immune response; analytical method; anti-PD-L1 antibodies; anti-PD1 antibodies; anti-cancer; base; cancer cell; cancer therapy; candidate selection; clinically relevant; cytotoxic; density; design; effective therapy; efficacy evaluation; humanized mouse; improved; in vivo; inhibitor/antagonist; kinase inhibitor; lead candidate; liver function; lung cancer cell; men; mouse model; nanoparticle; nanoparticle delivery; nanoparticle drug; nonhuman primate; novel; novel therapeutics; outcome prediction; particle; patient derived xenograft model; programmed cell death ligand 1; safety study; success; targeted delivery; targeted treatment; treatment effect; tumor; tumor growth; tumor microenvironment; uptake

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.

非小细胞肺癌（NSCLC）的治疗通常需要多种高毒性药物的组合， 药物和放射治疗，是不能治愈的。靶向PD-L1/PD-1的免疫检查点抑制剂（ICI）是 导致NSCLC治疗的范式转变，但5年生存率仍低于20%。 这一快速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ICI的疗效， NSCLC患者的结局。ARAC是建立在我们的核心纳米粒子平台，能够共同提供 多种治疗剂，同时在盐水中保持小尺寸（100 nm），适用于输注和肿瘤 积累申报的ARAC-02将联合递送polo样激酶1（PLK 1）靶向治疗（volasertib）， PD-L1抗体和免疫刺激剂CpG。Volasertib 1）选择性杀死癌细胞，2）调节 免疫抑制性肿瘤微环境，和3）上调癌细胞中的PD-L1表达， 在纳米颗粒上靶向递送PD-L1抗体的机会。CpG是寡核苷酸， 增强抗原呈递以产生肿瘤特异性T细胞。纳米颗粒含有非常高的 PD-L1抗体的表面密度（每个颗粒2000个），可促进与PD-L1分子的结合 在癌细胞上，随后是内化和PD-L1降解（与30倍游离PD-L1一样有效 抗体），释放制动器并允许T细胞攻击癌症。当给老鼠静脉注射时 在携带肺肿瘤的患者中，共递送volasertib和PD-L1抗体的纳米颗粒减少了必要的剂量， 每种药物的疗效提高5倍。将CpG添加到纳米结构中引发更大的适应性抗癌 在双侧NSCLC小鼠模型中的免疫，导致一些小鼠完全治愈。该平台还 在猴子身上是安全的。 在I期（目标1）中，将对ARAC-02进行优化，以加载volasertib、PD-L1抗体和CpG。材料 将针对大小、靶向特异性、在NSCLC细胞中的功效以及在小鼠中的功效和安全性进行筛选。 在II期，将评估最佳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）和与当前一线免疫疗法联合使用（目标3）。临床相关 将使用对ICI耐药的原位NSCLC小鼠模型，并将在 携带代表患者中异质性NSCLC的两种不同患者来源的肿瘤的人源化小鼠。 游离药物、单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 提供治愈性结局，特别是与当前ICI一起用于完全阻断时。ARAC-02可以 上调PD-L1水平，从而促进在广泛肿瘤类型中的疗效，而与基线PD无关。 L1水平。结果将是候选人的选择和关键数据对IND申请和临床试验。