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Tunneling Nanotube Inhibitors for Cancer Immunotherapy

用于癌症免疫治疗的隧道纳米管抑制剂

基本信息

批准号：
10735019
负责人：
Shiladitya Sengupta
金额：
$ 65.26万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2023-07-19 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735019
关键词：
3-Dimensional 4T1 Actins Autologous Binding Biopsy Breast Cancer Cell Cell Communication Cell Culture Techniques Cell Death Cell Survival Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Cryoelectron Microscopy Crystallography Dose Electrons Exhibits Genetic Genus Hippocampus Guanosine Triphosphate Phosphohydrolases Harvest Hour Human Image Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Memory Immunologics Immunotherapy In Vitro Infiltration Knock-out Label Lead Malignant Neoplasms Mediating Metabolic Minor Mitochondria Mus Nanotechnology Nanotubes Nature Normal tissue morphology Outcome Patients Penetration Pharmacology Physiology Play Publishing Research Role Safety Scanning Science Small Interfering RNA Structure T-Cell Activation T-Lymphocyte Testing Therapeutic Time Toxic effect Toxicokinetics Tumor Antigens Tumor Escape cancer cell cancer immunotherapy cell type cellular engineering effector T cell efficacy testing efficacy validation humanized mouse improved in vivo inhibitor insight knock-down meter mouse model nano nanoscale next generation novel overexpression programmed cell death ligand 1 programmed cell death protein 1 rational design response small molecule small molecule inhibitor survival outcome systemic toxicity therapeutic target trafficking tumor tumor immunology tumor progression

项目摘要

ABSTRACT In a recent study published in Nature Nanotechnology, we demonstrated that cancer cells form physical nanoscales tentacles (nanotubes) to connect with and harvest mitochondria from immune cells. Such mitochondria hijacking metabolically depleted the immune cells and augmented the cancer cells. These findings have significant implications as it emerges as a novel mechanism of immune evasion by cancer cells, which can limit the efficacy of immune checkpoint inhibitors. Here we propose to develop next- generation immunotherapies that can perturb this novel immune evasion phenomenon. We are specifically developing novel small molecule inhibitors of the exocyst complex, which we have implicated in the above phenomenon. Our preliminary results show that such small molecules can exert a powerful antitumor efficacy, augment classical immune checkpoint inhibitors and display an excellent safety profile. In Aim 1. We will synthesize and characterize exocyst inhibitors in vitro to test the hypothesis that rationally designed small molecule inhibitors of the exocyst complex can inhibit nanotube assembly. In Aim. 2. We will establish the safety pharmacology of exocyst inhibitors in vivo. In Aim 3, we will test the hypothesis that exocyst inhibitors can improve antitumor outcomes with immune checkpoint inhibitors. Achieving these aims will lead to fundamental insights into a new mechanism of cancer-immune cell communication. Our preliminary results indicate exocyst inhibitors can emerge as a new class of immunotherapy.

摘要在最近发表在《自然纳米技术》上的一项研究中，我们证明了癌细胞可以形成物理纳米尺度的触角（纳米管）连接和收获免疫细胞的线粒体。等线粒体劫持代谢耗尽免疫细胞并增加癌细胞。这些这些发现具有重要意义，因为它是癌症免疫逃避的一种新机制细胞，这可能限制免疫检查点抑制剂的功效。在这里，我们建议开发下一个- 产生免疫疗法，可以扰乱这种新的免疫逃避现象。我们特别开发新型的外囊复合物的小分子抑制剂，我们在上文中已经暗示了这一点现象我们的初步结果表明，这种小分子可以发挥强大的抗肿瘤作用，有效性，增强经典免疫检查点抑制剂，并显示出优异的安全性。在目标1中。我们将在体外合成和表征外囊抑制剂，以测试合理设计的假设，外囊复合物的小分子抑制剂可以抑制纳米管组装。在Aim。2.我们将建立外囊抑制剂的体内安全药理学。在目标3中，我们将检验外囊抑制剂可以改善免疫检查点抑制剂的抗肿瘤结果。实现这些目标将导致对癌症免疫细胞通讯新机制的基本见解。我们的初步结果表明外囊抑制剂可以作为一类新的免疫疗法出现。