Imaging Modulation of Immune Phenotype

免疫表型的成像调节

基本信息

批准号：
10548151
负责人：
Katherine W Ferrara
金额：
$ 64.14万
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/10548151
关键词：
Abbreviations Abraxane Acids Address Adverse event Agonist Animal Model Animals Biological Assay Biopsy Cancer Etiology Cells Characteristics Chemistry Clinical Treatment Clinical Trials Combined Modality Therapy Complex Data Dendritic Cells 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 Interferons Kidney Lectin Leukocytes Lymphoma Macrophage 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 biomaterial compatibility checkpoint therapy chemotherapy efficacy evaluation gastrointestinal gemcitabine immunoregulation improved in vivo lipophilicity 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

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，并发现 TLR NP 与 aCD40 结合， aPD-1 和 aCTL4（在新兴胰腺癌研究中缩写为 CP4）有效回归植入多部位侵袭性小鼠胰腺肿瘤。我们制定了多种战略并且特别关注 18 nm 可生物降解的多功能颗粒，结合了免疫调节肽、靶向肽和 Toll 样受体 (TLR) 激动剂。我们特别添加了免疫调节肽 PADRE（T 辅助肽）调节）和甘露糖（增强巨噬细胞摄取）以及 TLR7/8 激动剂（瑞喹莫特）前期工作。为了最大化有效负载，我们通过生物相容性单胶束纳米颗粒构建结合高效酯化和无金属点击反应，发现颗粒代谢物通肾清。在我们的初步研究中，TLR7/8-纳米粒子联合CP4治疗在高度转移、多部位植入性胰腺癌模型中增强反应（Kras+/LSL-G12D； Trp53+/LSL-R172H； Pdx1-Cre型号：缩写为KPC）。新的初步数据表明 TLR7/8 激动剂和 aCD40均对胰腺肿瘤细胞具有直接功效。 RNAseq 结果表明 TLR7/8 激动剂和 CD40 增强互补途径（CD40 的 C-凝集素（以及其他）和 TLR/干扰素对于 TLR 激动剂）。我们发现该组合可增强抗肿瘤白细胞、消退 KPC 肿瘤并响应者，100%在再次攻击时不会生长肿瘤。通过监测 OX40 表达（T 细胞标记物）激活），我们证明与其他涉及 aCD40 的免疫调节方法不同，T 细胞活性。我们同时开发了利用正电子发射监测 OX40 表达的能力以无创方式进行断层扫描。我们拟议工作的主要目标是推动纳米疗法策略转向人工翻译。因此，我们将评估啮齿类动物胰腺癌模型的疗效以及在更大的动物模型中的安全性。此外，我们将评估接受活检的患者样本胰腺癌以更好地表征免疫环境。我们有两个主要目标：1）发展系统性 T 细胞调节的有效策略的研究，以及 2) 将其与正电子相结合发射断层扫描成像和 RNA 测序以优化多组分方案。在目标 1 中，我们将确定最佳载体特性，通过 1a) 调节纳米颗粒来最大化 T 细胞调节特征并评估由此产生的功效，1b) 使用正电子发射断层扫描 (PET) 成像来量化全身注射的 NP 激动剂的积累，以及 1c) 通过剂量评估毒性升级和大型动物研究，导致 IND 申请。在目标 2 中，开发成像和体外利用 2a) OX40 PET 成像和 2b) 流式细胞术评估 T 细胞激活策略 RNA测序。