Imaging Modulation of Immune Phenotype

免疫表型的成像调节

基本信息

批准号：
10113064
负责人：
Katherine W Ferrara
金额：
$ 66.95万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10113064
关键词：
Abraxane Acids Address Adverse event Agonist Animal Model Animals Biological Assay Biopsy Cancer Etiology Cell physiology Cells Characteristics Chemistry Clinical Treatment Clinical Trials Combined Modality Therapy Complex Data Dendritic cell tumor Detection Development Diagnosis Dose Drug Kinetics Environment Esterification Extravasation Flow Cytometry Formulation Goals Head and Neck Cancer Image Immune Immune response ImmunoPET Immunophenotyping Immunotherapy Implant In Vitro Interferon Receptor Italy KPC model Kidney Lectin Leukocytes Lymphoma Malignant Neoplasms Malignant neoplasm of pancreas Mannose Metals Methods Modeling Modernization Monitor Monoclonal Antibodies Mus Myeloid-derived suppressor cells Nature OX40 PADRE 45 Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peptides Phenotype Polymers Positron-Emission Tomography Prognosis Property Protocols documentation Reaction Reporting Resistance Rodent Safety Sampling Site T cell response T-Cell Activation T-Lymphocyte TLR7 gene TNFRSF5 gene Techniques Testing Therapeutic Therapeutic Index Time Toll-like receptors Toxic effect Translations Unresectable Update Work adaptive immune response anti-CTLA4 anti-PD-1 base biomaterial compatibility checkpoint therapy chemotherapy efficacy evaluation gastrointestinal gemcitabine immunoregulation improved in vivo lipophilicity macrophage malignant breast neoplasm mortality mouse model nanoformulation nanoparticle nanoparticle delivery nanotherapeutic nanotherapy non-invasive monitor pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm particle preclinical study predicting response receptor resiquimod response scaffold small molecule specific biomarkers transcriptome sequencing translation to humans treatment optimization tumor tumor microenvironment uptake

Abraxane Acids Address Adverse event Agonist Animal Model Animals Biological Assay Biopsy Cancer Etiology Cell physiology Cells Characteristics Chemistry Clinical Treatment Clinical Trials Combined Modality Therapy Complex Data Dendritic cell tumor Detection Development Diagnosis Dose Drug Kinetics Environment Esterification Extravasation Flow Cytometry Formulation Goals Head and Neck Cancer Image Immune Immune response ImmunoPET Immunophenotyping Immunotherapy Implant In Vitro Interferon Receptor Italy KPC model Kidney Lectin Leukocytes Lymphoma Malignant Neoplasms Malignant neoplasm of pancreas Mannose Metals Methods Modeling Modernization Monitor Monoclonal Antibodies Mus Myeloid-derived suppressor cells Nature OX40 PADRE 45 Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peptides Phenotype Polymers Positron-Emission Tomography Prognosis Property Protocols documentation Reaction Reporting Resistance Rodent Safety Sampling Site T cell response T-Cell Activation T-Lymphocyte TLR7 gene TNFRSF5 gene Techniques Testing Therapeutic Therapeutic Index Time Toll-like receptors Toxic effect Translations Unresectable Update Work adaptive immune response anti-CTLA4 anti-PD-1 base biomaterial compatibility checkpoint therapy chemotherapy efficacy evaluation gastrointestinal gemcitabine immunoregulation improved in vivo lipophilicity macrophage malignant breast neoplasm mortality mouse model nanoformulation nanoparticle nanoparticle delivery nanotherapeutic nanotherapy non-invasive monitor pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm particle preclinical study predicting response receptor resiquimod response scaffold small molecule specific biomarkers transcriptome sequencing translation to humans treatment optimization tumor tumor microenvironment uptake

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项目摘要

Imaging and modulation of immunophenotype Most importantly, we have created TLR delivery nanotherapeutics and find that TLR NPs combined with aCD40, aPD-1 and aCTL4 (abbreviated as CP4 as in emerging pancreatic cancer studies) efficiently regressed implanted multisite invasive murine pancreatic tumors. We have developed multiple strategies and are particularly focused on 18 nm biodegradable, multi-functional particles that combine immune-modulating peptides, targeting peptides and toll-like receptor (TLR) agonists. We specifically included the immune modulating peptide PADRE (T helper modulation) and mannose (to enhance macrophage uptake) in addition to the TLR7/8 agonist (resiquimod) in preliminary work. To maximize payload, we built upon biocompatible unimicellar nanoparticles via the combination of highly efficient esterification and metal-free click reactions and find that the particle metabolites clear through the kidneys. In our preliminary studies, TLR7/8-nanoparticle treatment combined with CP4 enhanced response in a highly metastatic, multi-site implanted pancreatic cancer model (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre model: abbreviated as KPC). New preliminary data indicate that TLR7/8 agonists and aCD40 each have direct efficacy against pancreatic tumor cells. RNAseq results demonstrate that TLR7/8 agonists and CD40 enhance complementary pathways (C-lectin for CD40 (among others) and TLR/interferon for TLR agonists). We find that the combination enhances anti-tumor leukocytes, regresses KPC tumors and for responders, 100% do not grow tumor on re-challenge. By monitoring OX40 expression (a marker of T cell activation), we demonstrated that unlike other immune modulating approaches involving aCD40, T cells were activated. We have simultaneously developed the ability to monitor OX40 expression using positron emission tomography in a noninvasive fashion. Our primary goal in the proposed work is to move the nanotherapy strategy forward to human translation. As a result, we will evaluate efficacy in models of pancreatic cancer in rodents and safety in a larger animal model. Further, we will evaluate samples from patients undergoing biopsy for pancreatic cancer to better characterize the immune environment. We have 2 major goals: 1) the development of an effective strategy for systemically-administered T cell modulation and 2) combining this with positron emission tomographic imaging and RNA sequencing to optimize multi-component protocols. Within Aim 1, we will determine the optimal carrier properties to maximize T cell modulation by 1a) modulating nanoparticle characteristics and evaluating resulting efficacy, 1b) using positron emission tomography (PET) imaging to quantify accumulation of the systemically-injected NP agonists, and 1c) assessing toxicity through dose escalation and a large animal study, leading to IND filing. Within Aim 2, develop an imaging and in vitro assessment strategy for T cell activation by utilizing 2a) OX40 PET imaging and 2b) flow cytometry and RNAsequencing.

免疫表型的成像和调节最重要的是，我们创建了TLR递送纳米疗法，发现TLR NP与ACD40相结合， APD-1和ACTL4（如新兴胰腺癌研究中的CP4缩写为CP4）有效地植入了多站点侵入性鼠胰腺肿瘤。我们已经制定了多种策略，并且特别关注在18 nm的可生物降解的多功能颗粒上，结合了免疫调节肽，靶向肽和收费受体（TLR）激动剂。我们特别包括免疫调节肽Padre（T助手调制）和甘露糖（以增强巨噬细胞的吸收），除了在TLR7/8激动剂（resiquimod）外初步工作。为了最大化有效载荷，我们通过生物相容性的Unimicellar纳米颗粒建立高效酯化和无金属点击反应的组合，发现颗粒代谢物清除肾脏。在我们的初步研究中，TLR7/8纳米颗粒处理与CP4结合在高度转移性的多位植入胰腺癌模型（KRAS+/LSL-G12D）中增强了反应； TRP53+/LSL-R172H; PDX1-CRE模型：缩写为KPC）。新的初步数据表明TLR7/8激动剂和 ACD40对胰腺肿瘤细胞具有直接的功效。 RNASEQ结果表明TLR7/8 激动剂和CD40增强了互补途径（CD40的C-结构蛋白（除其他）和TLR/Interferon 对于TLR激动剂）。我们发现该组合可以增强抗肿瘤白细胞，回归KPC肿瘤，并用于响应者，100％不在重新挑战时肿瘤。通过监测OX40表达（T细胞的标记激活），我们证明了与其他涉及ACD40的免疫调节方法不同，T细胞是活性。我们同时开发了使用正电子发射监测OX40表达的能力以无创的方式进行断层扫描。我们在拟议工作中的主要目标是移动纳米疗法策略向前翻译。结果，我们将评估啮齿动物胰腺模型的功效和更大动物模型的安全性。此外，我们将评估接受活检的患者的样本胰腺癌更好地表征了免疫环境。我们有2个主要目标：1）发展针对全身管理T细胞调制的有效策略，以及2）将其与正电子结合发射断层成像和RNA测序以优化多组分协议。在目标1中，我们将确定最佳载体特性，以通过1A）调节纳米颗粒来最大化T细胞调制特征和评估结果功效，1B）使用正电子发射断层扫描（PET）成像为量化系统注射的NP激动剂的积累，1C）通过剂量评估毒性升级和一项大型动物研究，导致IND提交。在AIM 2中，开发成像和体外通过使用2A）OX40 PET成像和2B）流式细胞术和 rnasequencing。