Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer

用于胰腺癌图像引导治疗的基质穿透和免疫调节纳米颗粒

基本信息

批准号：
10747717
负责人：
Hui Mao
金额：
$ 2.81万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747717
关键词：
Binding Biological CAR T cell therapy CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene CXCR4 Receptors CXCR4 gene Cancer Patient Cancer cell line Carrying Capacities Cell Death Cell model Cell physiology Cells Combined Modality Therapy Cytotoxic T-Lymphocytes Dendritic Cells Detection Development Doctor of Philosophy Drug Delivery Systems Drug Targeting Encapsulated Engineering Evaluation Extracellular Matrix Funding Goals Human Hyaluronic Acid Immune Immune checkpoint inhibitor Immune response Immunotherapeutic agent Immunotherapy In Vitro Incubated Infiltration Interdisciplinary Study Investigation Lead Ligands Magnetic Resonance Imaging Magnetism Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mus Pancreas Parents Penetration Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacotherapy Phase Reporting Research Project Grants Research Training Resistance SCID Mice Small Business Technology Transfer Research Solid Solid Neoplasm Stromal Cells Stromal Neoplasm System T-Lymphocyte Therapeutic Agents Therapeutic Effect Transgenic Mice Treatment Efficacy Tumor Cell Line United States National Institutes of Health antitumor effect cancer cell cancer immunotherapy chemokine receptor chemotherapy chimeric antigen receptor T cells cytotoxic cytotoxicity effector T cell image guided therapy immune checkpoint immune function immune modulating agents immunogenic immunoregulation improved in vivo inhibitor iron oxide nanoparticle mesothelin mouse model nano nanoparticle nanoparticle delivery nanoparticle drug neoplastic cell novel novel strategies pancreatic cancer cells pancreatic cancer model pancreatic neoplasm patient derived xenograft model peptidomimetics pre-doctoral prevent programmed cell death ligand 1 programmed cell death protein 1 small molecule systemic toxicity targeted cancer therapy targeted delivery targeted treatment theranostics treatment response tumor tumor-immune system interactions

项目摘要

Project Summary Recent advances in targeted delivery of nanoparticle/drugs and CAR T cell therapy have shown promises in the development of novel approaches for overcoming resistance to chemo- and immunotherapy in pancreatic cancer. A major obstacle in CAR T therapy in pancreatic cancer is the presence of multiple barriers that prevent cytotoxic T cells reaching tumors and actively killing tumor cells. Dense tumor stromal cells and extracellular matrix create physical and biological barriers to trap T cells in the stroma and inhibit T cell function. There is an unmet need of effective approaches to improve delivery of CAR T cells in pancreatic cancer. Tumor targeted, stroma- penetrating theranostic iron oxide nanoparticles (IONPs) developed in the parent R01 project offer an opportunity to develop a combination therapy to improve targeted delivery and intratumoral distribution of CAR T cells and overall therapeutic responses. Our results showed that uPAR-targeted and stroma breaking ligand (ATFmmp14) can overcome stromal cellular and extracellular matrix barriers to enhance tumor delivery of nanoparticle-drugs and T cells in human pancreatic PDX and transgenic mouse tumor models. In this supplement research project, we hypothesize that the binding of uPAR targeted, stroma-penetrating IONPs carrying chemo- and immunotherapeutic agents to CAR T cells significantly enhances delivery of CAR T cells and chemotherapy drugs into pancreatic cancer. Immune checkpoint PD-L1 and CTLA4 blocking peptides conjugated on the IONPs further activate CAR T cell function. Those combined effects lead to a strong therapeutic response in pancreatic cancer and overcome therapy resistance. In the proposed study, we will first determine the effect of ATFmmp14- conjugated IONPs carrying a chemotherapy agent, SN38, on viability and cytotoxicity of anti-MUC16 and/or Mesothelin CAR T cells in vitro in human pancreatic cancer cell lines. Therapeutic effect of co-delivery of the targeted IONP/SN38 with CAR T cells will be evaluated in a pancreatic cancer PDX model in SCID mice (Aim 1). Next, we will develop a novel targeted and stroma-penetrating CAR T cell delivery system by backpacking with ATFmmp14-IONP/SN38 carrying PD-L1 and/or CTLA4 blocking peptides, mediated by a CXCR4 inhibitor (BL-8040), for overcoming resistance to chemo- and CAR T cell therapy in pancreatic cancer (Aim 2). The effect on targeted delivery of CAR T cells and therapeutic efficacy using the backpack system containing ATFmmp14- IONP/SN38/immune checkpoint inhibitors will be evaluated in the pancreatic cancer PDX model (Aim 2). We will then investigate the therapeutic effects of the targeted chemo- and immunotherapy IONP-CAR T cells on tumor cells, immune cells and tumor stroma immune microenvironment using a mouse anti-MUC16 CAR T cells in a transgenic mouse pancreatic cancer cell line derived mouse tumor model (Aim 2). Finally, the feasibility of MR imaging for tracking intratumoral delivery of targeted IONP backpacked CAR T cells will be determined in mouse tumor models (Aim 2). This supplement project will provide a diversity pre-doctoral candidate with multidisciplinary research training to develop a novel cancer immunotherapy and to complete PhD thesis study.

项目摘要纳米颗粒/药物和CAR T细胞疗法的靶向递送的最新进展已显示出有望开发了克服胰腺癌化学和免疫疗法的新方法。胰腺癌汽车治疗的主要障碍是存在多种障碍，可防止细胞毒性 T细胞到达肿瘤并主动杀死肿瘤细胞。致密的肿瘤基质细胞和细胞外基质会产生物理和生物学障碍，可捕获基质中的T细胞并抑制T细胞功能。有未满足的需求改善胰腺癌中汽车T细胞输送的有效方法。肿瘤靶向基质 - 父母R01项目中开发的穿透性毒氧化铁纳米颗粒（IONP）提供了机会开发一种联合疗法以改善靶向递送和汽车T细胞的肿瘤内分布和总体治疗反应。我们的结果表明，UPAR靶向和基质破裂配体（ATFMMP14）可以克服基质细胞和细胞外基质屏障，以增强纳米颗粒剂量的肿瘤递送人类胰腺PDX和转基因小鼠肿瘤模型中的T细胞。在这个补充研究项目中，我们假设UPAR的靶向，基质 - 渗透型离子体的结合携带化学和对CAR T细胞的免疫治疗剂显着增强了CAR T细胞的递送和化学疗法吸毒胰腺癌。免疫检查点PD-L1和CTLA4阻断肽在IONP上缀合的肽进一步激活CAR T细胞功能。这些综合效果导致胰腺的强烈治疗反应癌症和克服抗药性。在拟议的研究中，我们将首先确定ATFMMP14-的影响携带化学疗法剂SN38的共轭离子，抗MUC16和/或的可活力和细胞毒性人胰腺癌细胞系中的间皮素汽车T细胞体外。共同传递的治疗作用具有CAR T细胞的靶向IONP/SN38将在SCID小鼠的胰腺癌PDX模型中评估（AIM 1）。下一用ATFMMP14-IOMP/SN38携带PD-L1和/或CTLA4阻断肽，由CXCR4抑制剂介导（BL-8040），以克服胰腺癌中对化学和CAR T细胞疗法的抗性（AIM 2）。效果使用包含ATFMMP14-的背包系统的靶向递送和治疗功效 IONP/SN38/免疫检查点抑制剂将在胰腺癌PDX模型中进行评估（AIM 2）。我们然后将研究靶向化学和免疫疗法IONP-CAR T细胞对治疗作用肿瘤细胞，免疫细胞和肿瘤基质免疫微环境使用小鼠抗MUC16 CAR T细胞在转基因小鼠胰腺癌细胞系衍生的小鼠肿瘤模型中（AIM 2）。最后，可行性 MR成像用于跟踪靶向IONP背包CAR T细胞的肿瘤内输送小鼠肿瘤模型（AIM 2）。这个补充项目将为博士前候选人提供多样性多学科研究培训，以开发新的癌症免疫疗法并完成博士学位论文研究。