Targeting exosomal PDL1 to improve immunotherapy

靶向外泌体 PDL1 改善免疫治疗

基本信息

批准号：
10480847
负责人：
WEI GUO
金额：
$ 41.06万
依托单位：
WISTAR INSTITUTE
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：
2021-09-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480847
关键词：
Academia Biological Assay Biological Markers Blood Blood Circulation CD8-Positive T-Lymphocytes Caliber Cell physiology Cells Clinical Coculture Techniques Combined Modality Therapy Data Development Dimensions Encapsulated Foundations Future Goals Immune checkpoint inhibitor Immunologics Immunosuppression Immunotherapy In Vitro Individual Industry Infrastructure Intervention Knowledge Lipids Measurement Measures Mediating Melanoma Cell Metastatic Melanoma Methods Mus Mutation Myeloid Cells Nature Nivolumab Outcome Patient Selection Patient-Focused Outcomes Patients Plasma Play Resistance Role Sampling Sensitivity and Specificity Series Skin Cancer System T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Toxic effect Tumor Tissue Tumor-associated macrophages Tumor-infiltrating immune cells Validation Vesicle Work alternative treatment anti-CTLA4 antibodies anti-PD-1 anti-PD1 antibodies anti-PD1 therapy base biomarker development cancer type checkpoint inhibition clinical application clinical decision-making clinical development clinical diagnostics clinical practice clinically relevant exhaustion exosome experimental study extracellular humanized mouse immune checkpoint immune resistance improved improved outcome interest ipilimumab liquid biopsy macrophage melanoma mouse model nano-exosomes nanosized neoplastic cell novel novel therapeutic intervention patient derived xenograft model patient response patient stratification pembrolizumab personalized immunotherapy predicting response predictive marker predictive test prevent programmed cell death ligand 1 programmed cell death protein 1 responders and non-responders response tool treatment optimization tumor tumor growth tumor progression

项目摘要

Project Summary - Project 1 Immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies have revolutionized anti-tumor therapy for many types of cancers including metastatic melanoma. However, the patient response rates are low. Combined therapies such as ipilimumab and nivolumab produce a higher response rate but are associated with significant toxicities. A major unmet need is to develop quantitative assays that stratify patients who will respond to anti- PD-1 therapy to avoid unnecessary toxicities, and direct non-responders to alternative treatments. Such a pre- treatment or early on-treatment predictor would provide decision-enabling information to clinicians to optimize the treatment of melanoma patients. While there is enormous interest and intensive efforts from both academia and industry to identify predictors to response to ICI, the current biomarkers are suboptimal and early on- treatment biomarkers are not available for any cancer types. Exosomes are nano-sized vesicles secreted by cells to the extracellular milieu. We found that metastatic melanoma cells secrete exosomes enriched with PD- L1, which suppress the function of CD8+ T cells in circulation and facilitate tumor growth. In patients’ plasma, the level of circulating exosomal PD-L1 (“exPD-L1”) and its change during the course of anti-PD-1 treatment are associated with the patient response to anti-PD-1 therapy (Chen et al., Nature 2018). Most recently, we found that tumor associated macrophages (TAM) also secrete exosomes that carry PD-L1 (“TAM-exPD-L1”), which can be selectively and quantitatively measured in patient blood. TAM exosomes effectively suppress the proliferation and function of CD8 T cells. The overarching goals of Project 1 are to develop a quantitative liquid biopsy-based tool that enables clinicians to predict the patient response to ICI-based therapies, and to understand the role of TAM-derived exosomes in immune suppression. In Aim 1, we will test the hypothesis that exPD-L1, and especially TAM-exPD-L1, individually or in combination, are effective predictors of patient response to ICI. We perform the assays using a large multi-institutional validation set of patient samples across different major therapeutic contexts, taking advantage of the unique infrastructure SPORE offers. In Aim 2, we will systematically investigate the pivotal roles of TAM-derived exosomes in immune suppression using melanoma-macrophage co-culture system, humanized mouse system, and exosomes purified directly from patient tumor tissues. Together, our work will establish exosomal PD-L1 as a rationale-based clinically relevant stratifier that warrants future development for clinical diagnostics. The proposed study will also unveil a role of TAM exosomes in immune suppression, which will not only advance our understanding of immune suppression at new dimensions, but also helps develop novel therapeutic approaches to improve the treatment of patients with melanoma.

项目摘要 - 项目1 免疫检查点抑制剂（ICI）（例如抗PD-1抗体）已彻底改变了许多抗肿瘤疗法包括转移性黑色素瘤在内的癌症类型。但是，患者的反应率很低。合并诸如ipilimumab和nivolumab之类的疗法产生较高的缓解率，但与显着相关毒性。一个主要的未满足需求是开发定量测定，使对抗抗反应的患者分层 PD-1治疗以避免不必要的毒性，并直接对替代疗法进行无反应。这样的预先治疗或早期治疗预测指标将为临床医生提供确定性的信息以优化黑色素瘤患者的治疗。虽然两位学术界都有巨大的兴趣和强烈的努力和行业为了确定对ICI反应的预测因素，当前的生物标志物是次优的，早期的任何癌症类型都无法使用治疗生物标志物。外泌体是纳米大小的蔬菜细胞到细胞外环境。我们发现转移性黑色素瘤细胞富含PD- L1，抑制CD8+ T细胞在循环中的功能并促进肿瘤生长。在患者的血浆中，循环外泌体PD-L1（“ EXPD-L1”）及其在抗PD-1治疗过程中的变化是与患者对抗PD-1治疗的反应有关（Chen等，自然，2018年）。最近，我们发现肿瘤相关的巨噬细胞（TAM）也携带PD-L1（“ Tam-Expd-l1”）的秘密外泌体可以在患者血液中有选择和定量测量。 TAM外泌体有效抑制 CD8 T细胞的增殖和功能。项目1的总体目标是开发定量液体基于活检的工具，使临床医生能够预测患者对基于ICI疗法的反应，并可以了解TAM衍生的外泌体在免疫抑制中的作用。在AIM 1中，我们将检验以下假设 expd-l1，尤其是单独或组合的tam-expd-l1是患者的有效预测指标对ICI的反应。我们使用大型多机构验证的患者样本跨度执行ASSA 利用独特的基础设施孢子提供的不同主要治疗环境。在AIM 2中，我们将系统地研究使用TAM衍生外泌体在免疫抑制中使用的关键作用直接从患者肿瘤组织。总之，我们的工作将建立外泌体PD-L1作为基于临床的基本原理策略诊断的未来发展的阶层。拟议的研究还将推出免疫抑制中的TAM外泌体，这不仅会提高我们对免疫抑制的理解在新的维度，但也有助于开发新的治疗方法以改善患者的治疗与黑色素瘤。