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Engineered Nanoformulation for Immune-modulation in Cancer

用于癌症免疫调节的工程纳米制剂

基本信息

批准号：
10719487
负责人：
Rajagopal Ramesh
金额：
$ 54.31万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719487
关键词：
Address Animal Model Animals Antigens Antineoplastic Agents Antitumor Response Apoptotic Binding Proteins Binding Sites Breast Cancer Cell CTLA4 gene Cancer Biology Cancer Model Cancer Patient Cancer cell line Cell Cycle Arrest Cell Death Cell Proliferation Cell physiology Cells Cisplatin Clinical Data Dendrimers Development Disease Progression Drug resistance Embryo Engineering Exhibits Gene Delivery Genetic Growth Human Immune Immune checkpoint inhibitor Immune response Immunoglobulins Immunology Immunotherapy In Vitro Invaded Laboratories Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Messenger RNA Micrometastasis Modeling Molecular Molecular Target Mucins Mus Mutagens Neoplasm Metastasis Oncoproteins Pathology Pathway interactions Promoter Regions Protein Family Proteins Radiation therapy Radiosensitization Recurrent disease Reporting Research Personnel Resistance Signal Transduction Small Interfering RNA Survival Rate T cell response T-Lymphocyte TNFSF10 gene Testing Therapeutic Tissues Treatment Failure Treatment outcome Vision anti-PD-L1 anti-PD-L1 therapy anti-cancer anticancer activity cancer cell cancer immunotherapy cancer infiltrating T cells cancer therapy cell motility chemotherapy clinical translation effective therapy efficacy study immune checkpoint immunoregulation in vivo inhibitor innovation lipid nanoparticle lung cancer cell mRNA Expression member molecular targeted therapies multidisciplinary nanoengineering nanoformulation nanoparticle nanotherapy neoplastic cell novel novel therapeutic intervention novel therapeutics overexpression patient subsets pharmacologic pointed protein preclinical study programmed cell death ligand 1 programmed cell death protein 1 protein expression siRNA delivery statistics targeted cancer therapy targeted treatment tumor tumor eradication tumor growth tumor heterogeneity

项目摘要

Expression of immune check point (ICP) molecules on tumor cells and the host immune cells, especially T-cells present in the tumor milieu, negatively impact the cancer treatment outcome resulting in inefficient tumor eradication. Data also exist showing chemo- and radio- therapy induce ICP proteins on tumor cells and thereby contributing to inactivation of tumor infiltrating T-cells, resulting in the inability to host a robust antitumor response and culminating in treatment failure, and disease recurrence. Hence, understanding how a cancer drug impacts ICP will lead to development of new therapeutic strategies that can circumvent ICP-mediated treatment failure. One such approach is to incorporate immune check point inhibitors (ICPi) which can rekindle T-cell response and enhance the efficacy of anticancer drugs. Studies from the PI's laboratory and others have demonstrated genetic and pharmacologic inhibition of the human antigen R (HuR), an mRNA-binding protein that is overexpressed in human cancer cells, results in growth inhibition, reduction in metastasis, and in increased animal survival. While these findings support advancing HuR-targeted therapy for clinical translation, the PI's lab has recently made a serendipitous discovery showing siRNA- mediated silencing of HuR using a lipid-based nanoparticle (HuR-NP) induced programmed death-ligand (PD-L)1 expression in lung cancer cells. PD-L1 is one among several ICP proteins which when expressed by tumor cells suppress T-cell function. HuR-NP markedly induced PD- L1 mRNA and protein expression in human lung cancer cell lines. Molecular studies showed HuR binding site in the promoter region of PD-L1. Finally, a negative correlation between HuR and PD-L1 expression was observed in human lung cancer tissues. To our knowledge, apart from our own observation reported herein, there are no prior reports demonstrating the ability of HuR to regulate PD-L1 and testing of HuR-nanotherapy with PD-L1 immunotherapy for cancer. On the basis of our novel findings, we posit that combining HuR-nanotherapy with PD-L1 immunotherapy will demonstrate superior anticancer efficacy by eliciting strong immune response, and reducing disease recurrence. We will test our hypothesis with three aims: Aim 1. Determine the therapeutic benefit of LNP targeting HuR in combination with anti-PD-L1 therapy in vitro. Aim 2. Demonstrate LNP targeted HuR treatment in combination with PD-L1 immunotherapy in in vivo using lung tumor models elicits immune response and enhanced antitumor activity. Aim 3. Investigate the molecular mechanism by which LNP targeting HuR modulates PD-L1 expression in lung cancer cells.

免疫检查点分子在肿瘤细胞上的表达与宿主免疫细胞，特别是存在于肿瘤环境中的T细胞，对癌症治疗产生负面影响结果导致低效的肿瘤根除。也有数据显示化疗和放射治疗- 治疗诱导肿瘤细胞上的ICP蛋白，从而导致肿瘤失活渗透T细胞，导致无法产生强大的抗肿瘤反应，最终导致治疗失败，疾病复发。因此，了解抗癌药物是如何影响肝内胆汁淤积症将导致新的治疗策略的发展，可以绕过肝内胆汁淤积症的中介治疗失败。其中一种方法是加入免疫检查点抑制剂(Icpi)。可以重新激发T细胞反应，增强抗癌药物的疗效。来自PI实验室和其他实验室的研究表明，遗传和药理学抑制人类抗原R(HUR)，这是一种过表达的mRNA结合蛋白人类癌细胞，导致生长抑制、转移减少和增加动物的生存。虽然这些发现支持在临床上推进HUR靶向治疗翻译过来，PI的实验室最近偶然发现了siRNA- 利用脂基纳米粒(HUR-NP)诱导的程序化沉默HUR 死亡配体(PD-L)1在肺癌细胞中的表达PD-L1是几种ICP蛋白中的一种当被肿瘤细胞表达时，会抑制T细胞的功能。HUR-NP可明显诱导PD- L1基因在人肺癌细胞系中的表达分子研究表明 HUR结合位点位于PD-L1启动子区域。最后，HUR之间的负相关人肺癌组织中可见PD-L1的表达。据我们所知，除了从我们在此报告的观察来看，没有先前的报告表明 HUR调节PD-L1和检测HUR纳米疗法与PD-L1免疫疗法对癌症的治疗。根据我们的新发现，我们假设将Hur纳米疗法与PD-L1相结合免疫疗法将通过激发强大的免疫来展示优越的抗癌效果反应，并减少疾病复发。我们将用三个目标来检验我们的假设：目标1。确定靶向HUR的LNP联合抗PD-L1治疗的疗效在试管中。目的2.展示LNP靶向HUR联合PD-L1治疗利用肺肿瘤模型进行体内免疫治疗可引起免疫反应和增强抗肿瘤活性。目的3.探讨LNP靶向HUR的分子机制调节肺癌细胞中PD-L1的表达。