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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：
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
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/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

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.

使用纳米化学疗法触发对胰腺导管腺癌的免疫反应