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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：
10654816
负责人：
Andre Elias Nel
金额：
$ 51.28万
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/10654816
关键词：
Adjuvant Adoptive Transfer Agonist Antibodies Antigen-Presenting Cells Blocking Antibodies C-terminal CXCR4 gene Cell Death Induction 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 alphaVbeta3 Integrins Intervention Lipid Bilayers Lipids Liver Malignant Neoplasms Malignant neoplasm of pancreas Mediating Memory Metabolic Pathway Metastatic Adenocarcinoma Metastatic Neoplasm to the Liver 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 Penetration Peptides Periodicity Pharmaceutical Preparations Pharmacologic Substance Primary Neoplasm Prodrugs Research Resistance Role Science Series Silicon Dioxide Site Solid Stimulator of Interferon Genes Stimulus Stromal Cell-Derived Factor 1 T cell response T memory cell T-Lymphocyte Techniques Testing Therapeutic 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 improved inhibitor innovation irinotecan metastasis prevention migration mortality nano nanocarrier nanoparticle nanoparticle delivery nanopolymer neoantigens novel strategies overexpression oxaliplatin pancreatic ductal adenocarcinoma model prevent programmed cell death protein 1 programs 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.

使用纳米化疗触发胰腺导管腺癌的免疫反应（PDAC）推出了一种克服免疫治疗的强大障碍的新方法，包括免疫治疗的不良障碍免疫原性、低新抗原负荷、基质干扰（“T 细胞排斥”）、过度表达吲哚胺 2,3-双加氧酶 (IDO-1) 以及肝脏有利于转移的免疫特权环境传播。我们的初步数据表明，脂质双层包覆的介孔二氧化硅纳米粒子（二氧化硅体）通过提供预筛选的诱导免疫原性细胞死亡（ICD）提供有效的平台化疗药物到达 PDAC 部位。 ICD促进内源性肿瘤抗原的呈递细胞，提出了这样的假设：ICD 提供了一种有前途的内源性疫苗接种方法来产生“热” 肿瘤微环境（TME）可以通过共同递送干扰区域的药物来传播过度表达的免疫抑制途径。 IDO-1、CXCR4 抑制剂可以靶向这些途径（T 细胞排除）和糖原合酶激酶 3（控制 PD-1 表达）。我们还建议 ICD 诱导的记忆 T 细胞和“干扰素刺激剂”的递送可以减少转移扩散基因”（STING）可激动肝脏中的耐受性抗原呈递细胞。我们的长期目标跨学科的努力是开发一个化学免疫治疗平台，用于通过二氧化硅体与免疫检查点和 T 细胞排除途径 (CXCR4) 抑制剂同时存在。目标包括使用创新载药和胆固醇缀合前药来合成可用于在 ICD 刺激和抑制剂之间获得最佳协同作用的二氧化硅体原位和基因工程 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协同作用的机制基础。我们将使用整合素靶向、肿瘤穿透的 iRGD 肽通过转胞吞途径增强药物递送。我们还将构建聚合物纳米载体来传递 STING 激动剂，以防止转移扩散到肝。理由是使用 ICD 方法生成“热”肿瘤环境将有助于联合免疫疗法可改善 PDAC 死亡率。我们计划通过追求来检验我们的假设具体目标如下：目标 1：为 PDAC 开发纳米化学免疫治疗平台利用内源性（ICD 介导的）治疗方法加上干扰区域过度表达免疫检查点通路产生“热”肿瘤环境。目标2：增强免疫治疗通过使用整合素靶向、肿瘤穿透 iRGD 肽和开发 ICD 平台的影响二氧化硅体通过传递 CXCR4 抑制剂来干扰基质中的 T 细胞排斥。目标#3：通过 STING 纳米颗粒重新编程肝脏 APC 的免疫抑制作用，促进根除 PDAC 转移是由 ICD 诱导的二氧化硅体产生的记忆 T 细胞引起的。