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

基本信息

批准号：
10734087
负责人：
Worapol Ngamcherdtrakul
金额：
$ 93.28万
依托单位：
PDX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10734087
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 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 Histology Human Immune Immune Evasion Immune checkpoint inhibitor Immunocompetent Immunohistochemistry Immunologic Stimulation Immunotherapy 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 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 Woman adaptive immune response analytical method anti-PD-L1 antibodies anti-PD1 antibodies anti-cancer cancer cell cancer survival cancer therapy candidate selection clinically relevant cytotoxic density design effective therapy efficacy evaluation humanized mouse immune cell infiltrate immune stimulant immune stimulatory agent immunoregulation improved in vivo inhibitor kinase inhibitor lead candidate liver function lung cancer cell men mouse model nano nanoparticle nanoparticle delivery nanoparticle drug nonhuman primate novel novel therapeutics outcome prediction particle patient derived xenograft model polo-like kinase kinase 1 programmed cell death ligand 1 safety study success targeted delivery targeted treatment treatment effect tumor tumor growth tumor microenvironment uptake

项目摘要

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.

通常需要处理许多高毒性的非小细胞肺癌（NSCLC）的治疗药物和放射疗法无法治愈。靶向PD-L1/PD-1的免疫检查点抑制剂（ICI）为导致NSCLC治疗的范式转移，但5年生存率仍低于20％。此快速轨道SBIR应用程序旨在开发一种新型的纳米免疫疗法（称为ARAC-抗原释放剂和检查点抑制剂）可以大大提高ICI的功效 NSCLC患者的结果。 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剂，同时保持小尺寸的盐水（100 nm），适合输注和肿瘤积累。拟议的ARAC-02将共同使用类似polo的激酶1（PLK1）靶向疗法（volasertib）， PD-L1抗体和免疫刺激的CpG。伏拉替伯1）选择性杀死癌细胞，2）调节免疫抑制肿瘤微环境，3）上调癌细胞中的PD-L1表达，提供纳米颗粒上使用PD-L1抗体靶向递送的机会。 CpG是一种寡核苷酸增强抗原表现以产生肿瘤特异性T细胞。纳米颗粒包含很高的 PD-L1抗体的表面密度（每个颗粒两千个），促进与PD-L1分子结合在癌细胞上，然后进行内在化和PD-L1降解（与30倍的游离PD-L1一样有效抗体），释放制动器并允许T细胞攻击癌症。当静脉注射给小鼠时轴承肺部肿瘤，纳米颗粒共递交volasertib和PD-L1抗体可降低必要的剂量为每种药物的功效提高5倍。将CPG添加到纳米结构中，触发更大的自适应抗癌者双侧NSCLC小鼠模型中的免疫力，导致某些小鼠的完整治疗方法。平台也是发现在猴子中很安全。在第一阶段（AIM 1）中，将优化ARAC-02用于加载volasertib，PD-L1抗体和CpG。材料将筛选尺寸，靶向特异性，NSCLC细胞的功效以及小鼠的功效和安全性。在第二阶段，将评估最佳ARAC-02的药代动力学，生物分布，功效和安全性单独使用（AIM 2），以及与当前的一线免疫疗法（AIM 3）结合使用。临床相关将利用对ICI具有抗性的原位NSCLC鼠标模型，并将在人性化小鼠带有两种不同的患者肿瘤，这些肿瘤代表患者的异质NSCLC。免费药物，单毒的纳米颗粒和一线免疫疗法将用作基准。由于其刺激自适应免疫反应的各个步骤的独特能力，预计ARAC-02将会提供治愈的结果，尤其是与当前ICI一起用于完全阻塞时。 ARAC-02可以上调PD-L1水平，从而在广泛的肿瘤类型中促进功效，而不论基线PD-L1水平如何。结果将是针对IND应用和临床试验的候选选择和关键数据。