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

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

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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的表达细胞，尤其是肿瘤环境中存在的T细胞，对癌症治疗产生负面影响结果导致消除肿瘤效率低下。还存在数据，显示了化学和无线电 - 治疗在肿瘤细胞上诱导ICP蛋白，从而导致肿瘤失活浸润T细胞，导致无法举办强大的抗肿瘤反应并在治疗失败和疾病复发。因此，了解癌症药物如何影响 ICP将导致发展新的治疗策略，以规避ICP介导的治疗失败。一种方法是结合免疫检查点抑制剂（ICPI）可以重新点燃T细胞反应并增强抗癌药物的功效。 PI的实验室和其他研究表明了遗传和药理学的研究抑制人类抗原R（HUR），一种mRNA结合蛋白，过表达人类癌细胞，导致生长抑制，转移减少并增加动物生存。尽管这些发现支持推进临床预先定位的疗法翻译，PI的实验室最近进行了偶然发现，显示了sirna- 使用基于脂质的纳米颗粒（HUR-NP）诱导编程的介导的HUR沉默肺癌细胞中的死亡配体（PD-L）1表达。 PD-L1是几种ICP蛋白之一当肿瘤细胞表达时，抑制T细胞功能。 hur-np明显诱导了PD- L1 mRNA和人肺癌细胞系中的蛋白质表达。分子研究表明 PD-L1启动子区域中的HUR结合位点。最后，HUR之间存在负相关在人肺癌组织中观察到PD-L1表达。据我们所知，分开从本文报告的我们自己的观察结果中，没有先前的报告证明 HUR调节PD-L1和对癌症的PD-L1免疫疗法测试HUR-纳米疗法。根据我们的新发现，我们认为将Hur-Nananotherapy与PD-L1相结合免疫疗法将通过引起强免疫表现出优势抗癌功效反应并减少疾病复发。我们将以三个目的检验我们的假设：目标1。确定LNP靶向HUR与抗PD-L1治疗的治疗益处体外。 AIM 2。证明LNP靶向HUR治疗与PD-L1结合使用肺肿瘤模型在体内免疫疗法会引起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。