Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy

使用纳米平台进行胰腺癌免疫治疗

基本信息

批准号：
10058189
负责人：
Andre Elias Nel
金额：
$ 55.31万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10058189
关键词：
Address Adjuvant Adoptive Transfer Agonist Antibodies Antigen-Presenting Cells Blocking Antibodies C-terminal CXCL12 gene CXCR4 gene Cells Cholesterol Combination immunotherapy Custom Cytotoxic T-Lymphocytes Data Dendritic Cells Desmoplastic Development Dinucleoside Phosphates Drug Combinations Drug Delivery Systems Duct (organ) structure Encapsulated Environment Exclusion Failure Gene Delivery Generations Genetic Engineering Genetic Transcription Glycogen Synthase Kinase 3 Glycolates Goals Immune Immune checkpoint inhibitor Immune response Immuno-Chemotherapy Immunologics Immunosuppression Immunotherapy Innate Immune System Integrin alpha Chains Integrin alphaVbeta3 Integrins Intervention Lead Lipid Bilayers Lipids Liver Malignant Neoplasms Malignant neoplasm of pancreas Mediating Memory Metabolic Pathway Metastatic Adenocarcinoma Metastatic Neoplasm to the Liver Modeling Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Neuropilin-1 Organ Outcome Study PD-1 pathway PD-1/PD-L1 PDL1 pathway Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peptides Periodicity Pharmaceutical Preparations Pharmacologic Substance Polymers Primary Neoplasm Prodrugs Research Resistance Role Science Series Silicon Dioxide Site Solid Stimulator of Interferon Genes Stimulus T cell response T memory cell T-Lymphocyte Techniques Testing Time Tryptophan 2,3 Dioxygenase Tumor Antigens Tumor-associated macrophages Vaccination alternative treatment cancer cell cancer immunotherapy cancer site checkpoint receptors chemotherapeutic agent chemotherapy design experimental study immune checkpoint immunogenic cell death immunogenicity immunological status inhibitor/antagonist innovation irinotecan metastasis prevention mortality nano nanocarrier nanoparticle nanoparticle delivery neoantigens novel strategies overexpression oxaliplatin prevent programmed cell death protein 1 receptor recruit response side effect small molecule inhibitor success synergism targeted delivery transcytosis treatment strategy tumor tumor microenvironment uptake

项目摘要

The use of nano-enabled chemotherapy to trigger an immune response to pancreatic ductal adenocarcinoma (PDAC) introduces a novel approach for overcoming robust barriers to immunotherapy, including poor immunogenicity, low neoantigen burden, stromal interference (“T-cell exclusion”), overexpression of indoleamine 2,3-dioxygenase (IDO-1), and the immune privileged environment of the liver favoring metastatic spread. Our preliminary data show that lipid-bilayer coated mesoporous silica nanoparticles (silicasomes) provide an effective platform for inducing immunogenic cell death (ICD) by delivering prescreened chemotherapeutic agents to the PDAC site. ICD promotes the presentation of endogenous tumor antigens cells, raising the hypothesis that ICD offers a promising endogenous vaccination approach to generate a “hot” tumor microenvironment (TME) that can be propagated by co-delivery of drugs interfering in regionally overexpressed immunosuppressive pathways. These pathways can be targeted by inhibitors of IDO-1, CXCR4 (T-cell exclusion) and glycogen synthase kinase 3 (which controls PD-1 expression). We also propose that metastatic spread can be reduced by ICD-induced memory T-cells and delivery of “stimulator of interferon genes” (STING) agonists to tolerogenic antigen presenting cells in the liver. The long-term goal of our interdisciplinary efforts is to develop a chemo-immunotherapy platform for delivery of ICD stimuli by the silicasome contemporaneous with inhibitors of immune checkpoint and T-cell exclusion pathways (CXCR4). The objectives include the use of innovative drug loading and cholesterol-conjugated prodrugs to synthesize silicasomes that can be used to obtain the best synergy between ICD stimuli and inhibitors of immunosuppressive pathways in orthotopic and genetic engineered PDAC models. This requires research discovery into the mechanistic basis of synergy between ICD and regional immune escape pathways. We will use an integrin-targeting, tumor-penetrating iRGD peptide to enhance drug delivery by a transcytosis pathway. We will also construct polymeric nanocarriers to deliver STING agonists for preventing metastatic spread to the liver. The rationale is that the use of an ICD approach to generate a “hot” tumor environment will facilitate combination immunotherapy with improvement of PDAC mortality. We plan to test our hypothesis by pursuing the following specific aims: Aim 1: To develop a nano-enabled chemo-immunotherapy platform for PDAC that utilizes an endogenous (ICD-mediated) treatment approach plus interference in regionally overexpressed immune checkpoint pathways to generate a “hot” tumor environment. Aim 2: To enhance the immunotherapy impact of the ICD platform by using integrin-targeting, tumor-penetrating iRGD peptides and developing a silicasome that interferes in T-cell exclusion in the stroma through the delivery of CXCR4 inhibitors. Aim #3: To reprogram the immune suppressive effects of liver APC by STING nanoparticles that promote eradication of PDAC metastases by the memory T-cells generated by ICD-inducing silicasomes.

使用纳米支持的化学疗法来引发对胰腺导管腺癌的免疫响应（PDAC）引入了一种克服免疫疗法的强大障碍的新方法，包括差免疫原性，新抗原伯恩，基质干扰（“ T细胞排除”），过表达吲哚胺2,3-二加氧酶（IDO-1）和肝脏的免疫特权环境有利于转移传播。我们的初步数据表明，脂质双层涂层介孔二氧化硅纳米颗粒（有机体）通过交付预筛选，为诱导免疫原性死亡（ICD）提供有效的平台 PDAC位点的化学治疗剂。 ICD促进内源性肿瘤抗原的呈现细胞，提出了ICD提供了一种有望的内源性疫苗接种方法来产生“热”的假设肿瘤微环境（TME），可以通过干扰区域的药物进行传播过表达的免疫抑制途径。这些途径可以由IDO-1，CXCR4的抑制剂靶向（T细胞排除）和糖原合酶激酶3（控制PD-1表达）。我们还建议通过ICD诱导的记忆T细胞和“干扰素的刺激剂”的递送，可以减少转移扩散基因”（sting）激动剂，用于肝脏中耐受性抗原的细胞。我们的长期目标跨学科的努力是开发一个化学免疫疗法平台，用于通过当代硅体具有免疫定位和T细胞排除途径（CXCR4）的抑制剂。这些物体包括使用创新的药物加载和胆固醇偶联的前药来合成可用于获得ICD刺激和抑制剂之间最佳协同作用的硅胶。原位和基因工程PDAC模型中的免疫抑制途径。这需要研究发现ICD和区域免疫逃逸途径之间的协同作用。我们将使用靶向整联蛋白靶向肿瘤的IRGD肽来通过转胞胞病症途径增强药物递送。我们还将构建聚合物纳米载体，以提供刺痛的激动剂，以防止转移扩散到肝。理由是使用ICD方法来产生“热”肿瘤环境将有助于联合免疫疗法与PDAC死亡率的改善。我们计划通过追求来检验我们的假设以下具体目的：目标1：为PDAC开发一个支持纳米的化学免疫疗法平台利用内源性（ICD介导的）治疗方法加上区域过表达的干扰免疫检查点途径产生“热”肿瘤环境。目标2：增强免疫疗法 ICD平台通过使用整合素靶向，肿瘤渗透IRGD的影响并开发一个通过递送CXCR4抑制剂，会干扰基质中T细胞排除的硅化体。目标＃3：到通过刺激纳米颗粒来重新编程肝APC的免疫抑制作用由ICD诱导硅胶产生的记忆T细胞的PDAC转移。