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

• 批准号: 10417161
• 负责人: Andre Elias Nel
• 金额: $ 52.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10417161
• 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; 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; innovation; irinotecan; metastasis prevention; mortality; nano; nanocarrier; nanoparticle; nanoparticle delivery; neoantigens; novel strategies; overexpression; oxaliplatin; pancreatic ductal adenocarcinoma model; 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

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.

使用纳米使能化疗引发对胰腺导管腺癌的免疫应答 （PDAC）介绍了一种新的方法，用于克服免疫治疗的强大障碍， 免疫原性、低新抗原负荷、基质干扰（“T细胞排斥”）、过表达 吲哚胺2，3-双加氧酶（IDO-1）和肝脏的免疫特权环境有利于转移性肝癌的发生。 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） 通过递送预筛选的细胞因子， 化疗剂的PDAC位点。ICD促进内源性肿瘤抗原的呈递 细胞，提出了一个假设，即ICD提供了一种有前途的内源性疫苗接种方法，以产生“热” 肿瘤微环境（TME），可以通过共同递送药物干扰区域性 过度表达的免疫抑制途径。这些途径可以通过IDO-1、CXCR 4和CXCR 4的抑制剂靶向。 （T细胞排斥）和糖原合成酶激酶3（其控制PD-1表达）。我们亦建议 通过ICD诱导记忆T细胞和递送“干扰素刺激剂”可以减少转移性扩散 在肝脏中，“STING”基因激动剂与致耐受性抗原呈递细胞结合。我们的长期目标是 跨学科的努力是开发一个化学免疫治疗平台，通过ICD刺激的传递， 二氧化硅体与免疫检查点和T细胞排斥途径（CXCR 4）的抑制剂同时存在。 目标包括使用创新的药物负载和胆固醇缀合的前药来合成 可以用于获得ICD刺激物和ICD抑制剂之间的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iRGD肽来增强通过胞吞转运途径的药物递送。 我们还将构建聚合物纳米载体来递送STING激动剂，以防止转移性扩散到肿瘤。 肝脏基本原理是使用ICD方法产生“热”肿瘤环境将促进 联合免疫治疗改善PDAC死亡率。我们计划通过追踪 以下具体目标：目标1：开发用于PDAC的纳米使能的化学免疫治疗平台， 利用内源性（ICD介导的）治疗方法加上干扰区域性过表达的 免疫检查点途径来产生“热”肿瘤环境。目的2：加强免疫治疗 ICD平台的影响，通过使用整合素靶向，肿瘤穿透iRGD肽和开发一种 二氧化硅体，其通过递送CXCR 4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， 通过ICD诱导二氧化硅体产生的记忆T细胞的PDAC转移。