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（ICP）分子在肿瘤细胞和宿主免疫上的表达细胞，尤其是肿瘤环境中存在的 T 细胞，会对癌症治疗产生负面影响结果导致肿瘤根除效率低下。数据还显示化学和放射治疗疗法在肿瘤细胞上诱导 ICP 蛋白，从而有助于肿瘤失活浸润 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，了解抗癌药物如何影响 ICP 将导致新的治疗策略的开发，从而规避 ICP 介导的治疗失败。其中一种方法是结合免疫检查点抑制剂（ICPi）它可以重新激发T细胞反应并增强抗癌药物的功效。 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 mRNA 结合蛋白，在人类癌细胞，导致生长抑制、转移减少和增加动物的生存。虽然这些发现支持推进 HuR 靶向治疗的临床翻译后，PI 的实验室最近偶然发现了 siRNA- 使用基于脂质的纳米颗粒 (HuR-NP) 介导的 HuR 沉默肺癌细胞中死亡配体 (PD-L)1 的表达。 PD-L1 是几种 ICP 蛋白之一当肿瘤细胞表达时，它会抑制 T 细胞功能。 HuR-NP 显着诱导 PD- 人肺癌细胞系中 L1 mRNA 和蛋白的表达。分子研究表明 HuR 结合位点位于 PD-L1 启动子区域。最后，HuR 之间呈负相关在人肺癌组织中观察到PD-L1的表达。据我们所知，除了根据我们自己在此报告的观察，之前没有报告表明有能力 HuR 调节 PD-L1 并测试 HuR 纳米疗法与 PD-L1 癌症免疫疗法。基于我们的新发现，我们认为将 HuR 纳米疗法与 PD-L1 相结合免疫疗法将通过引发强大的免疫来证明卓越的抗癌功效反应，并减少疾病复发。我们将通过三个目标来检验我们的假设：目标 1。确定靶向 HuR 的 LNP 与抗 PD-L1 疗法相结合的治疗益处体外。目标 2. 展示 LNP 靶向 HuR 联合 PD-L1 治疗使用肺肿瘤模型进行体内免疫治疗可引发免疫反应并增强抗肿瘤活性。目标3.研究LNP靶向HuR的分子机制调节肺癌细胞中的 PD-L1 表达。