Chemotherapy delivery with nanoparticles for targeted induction of immunogenic cell death

使用纳米粒子进行化疗，靶向诱导免疫原性细胞死亡

基本信息

批准号：
10247756
负责人：
Yoon Yeo
金额：
$ 40.8万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247756
关键词：
Affect Animal Model Animals Benchmarking Biodistribution Blood Circulation Cancer Patient Cancer Remission Cell Death Induction Cells Complement Cytotoxic T-Lymphocytes Development Disease remission Dose Dose-Limiting Drug Carriers Drug Delivery Systems Drug Kinetics Endothelium Evaluation Formulation Goals Grant Immune Immune system Immunity Immunocompromised Host Immunologic Memory Immunotherapy Ionizing radiation Label Ligands Literature Methods Mission Molecular Oncolytic viruses Paclitaxel Patients Pattern Performance Pharmaceutical Preparations Public Health Radiation Radiobiology Regimen Research Research Personnel Resources Role Safety Signal Transduction Small Interfering RNA Surface System T-Lymphocyte Therapeutic Toxic effect Toxicity due to chemotherapy Tumor Antibodies Tumor Antigens Tumor Immunity Tumor Suppression United States National Institutes of Health Variant anti-PD-1/PD-L1 anti-PD-L1 antibodies anti-cancer anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy chemotherapy clinical translation drug testing human disease immune checkpoint blockade immunogenic cell death immunogenicity improved in vivo innovation nanomedicine nanoparticle nanoparticle delivery nanoparticle drug neoantigens neoplastic cell novel therapeutics pharmacokinetics and pharmacodynamics polyphenol prevent programmed cell death ligand 1 response side effect systemic toxicity tumor tumor growth tumor immunology tumor microenvironment uptake

项目摘要

ABSTRACT Immune checkpoint blockade (ICB) aims to reactivate cytotoxic T-cell activities against tumors. Current ICB therapy has had a dramatic therapeutic impact, but only about 20% of patients have long-term tumor-free survival. A potential reason for the limited response rate is the lack of dominant neoantigens for T-cell recogni- tion. Several chemotherapeutic drugs have been identified as effective inducers of immunogenic cell death (ICD) and actively investigated in combination with ICB agents as off-label indications. However, a main chal- lenge in using chemotherapy as an ICD inducer is the dose-limiting side effects, including the toxicity to im- mune cells that will directly compromise cancer immunotherapy. In order to enhance ICB with ICD-inducing chemotherapy, a delivery system that specifically and efficiently affect tumor cells is necessary. With the ongo- ing R01 support (R01EB017791) we have developed nanoparticle (NP) systems with good circulation stability and high drug loading capacity that deliver more chemotherapeutic drugs to tumors and achieve greater anti- tumor efficacy relative to commercial benchmark products. We have also demonstrated that localized ionizing radiation (IR) further increased NP delivery to tumors. In this renewal application, we propose to use the NPs and IR to enhance their potential to induce ICD in tumors thereby sensitizing the tumors to ICB ther- apy. Our central hypothesis is that NPs will concentrate the drug in tumors without increasing systemic toxicity to induce ICD and help retain the released damage-associated molecular patterns and tumor antigens to gen- erate durable anti-tumor immune responses. We will combine NPs with high drug loading capacity and good circulation stability as well as surface modifiers that have contributed to in vivo performance of NPs in order to obtain optimal NPs for tumor delivery and intracellular uptake and retention. The activity of ICD-inducing NPs will be evaluated via the ability to promote anti-tumor immune responses (Aim 1); and their anti-cancer effect will be evaluated in combination with local ionizing radiation (Aim 2). To investigate the contribution of ICD-in- ducing NPs to ICB therapy, they will be combined with siRNA targeting PD-L1 or anti-PD-1/PD-L1 antibodies and evaluated in animal models of tumors with known (in)sensitivity to immunotherapy (Aim 3). The innovative aspect of this strategy is that it explores the untapped utility of NPs as a way of increasing the potential of chemotherapy to induce ICD and the role of carriers in cancer immunotherapy. With successful completion of this project, we expect to have developed a new therapeutic regimen with durable anti-cancer effects and high complete remission rates.

抽象的免疫检查点阻断 (ICB) 旨在重新激活细胞毒性 T 细胞对抗肿瘤的活性。当前的 ICB 疗法产生了巨大的治疗效果，但只有约 20% 的患者能够长期无肿瘤生存。反应率有限的一个潜在原因是缺乏 T 细胞识别的显性新抗原。。几种化疗药物已被确定为免疫原性细胞死亡的有效诱导剂 (ICD) 并积极研究与 ICB 药物联合作为标签外适应症。然而，一个主要挑战是使用化疗作为 ICD 诱导剂的一个难题是剂量限制性副作用，包括对免疫细胞的毒性。鼠细胞将直接损害癌症免疫治疗。为了通过 ICD 诱导增强 ICB 化疗，一种特异性、有效地影响肿瘤细胞的输送系统是必要的。随着持续的- 通过R01支持（R01EB017791），我们开发了具有良好循环稳定性的纳米颗粒（NP）系统高载药量，可以向肿瘤输送更多的化疗药物，达到更好的抗肿瘤作用相对于商业基准产品的肿瘤疗效。我们还证明了局部电离辐射 (IR) 进一步增加了 NP 向肿瘤的递送。在此续订申请中，我们建议使用 NP 和IR增强它们在肿瘤中诱导ICD的潜力，从而使肿瘤对ICB热敏化。阿比。我们的中心假设是纳米粒子将药物集中在肿瘤中而不增加全身毒性诱导 ICD 并帮助保留释放的损伤相关分子模式和肿瘤抗原产生持久的抗肿瘤免疫反应。我们将高载药量和良好的纳米颗粒结合起来循环稳定性以及表面改性剂有助于纳米粒子的体内性能，以便获得用于肿瘤递送以及细胞内摄取和保留的最佳纳米颗粒。 ICD 诱导 NP 的活性将通过促进抗肿瘤免疫反应的能力进行评估（目标 1）；及其抗癌作用将结合局部电离辐射进行评估（目标 2）。调查 ICD 的贡献将 NP 引入 ICB 治疗，它们将与靶向 PD-L1 的 siRNA 或抗 PD-1/PD-L1 抗体相结合并在已知对免疫疗法不敏感的肿瘤动物模型中进行评估（目标 3）。创新的该战略的一个方面是它探索了纳米颗粒的未开发效用，以此作为增加纳米颗粒潜力的一种方式。化疗诱导 ICD 以及携带者在癌症免疫治疗中的作用。随着顺利完成在这个项目中，我们期望开发出一种具有持久抗癌效果和高抗癌效果的新治疗方案。完全缓解率。