Hematopoietic stem cells overcome treatment resistance to PD-1 blockade against brain tumors

造血干细胞克服了针对脑肿瘤的 PD-1 阻断疗法的耐药性

基本信息

批准号：
10260393
负责人：
Catherine T Flores
金额：
$ 33.36万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260393
关键词：
Adjuvant Anatomy Antigens Beds Bone Marrow Brain Brain Neoplasms CD8-Positive T-Lymphocytes Cell Therapy Cell physiology Cells Clinical Clinical Research Cross-Priming Data Dendritic Cells Development Disease Disease Progression Engraftment Family Frequencies Gene Expression Profile Genetic Glioblastoma Glioma Goals Hematopoietic stem cells Immune Immune checkpoint inhibitor Immune system Immunotherapeutic agent Immunotherapy Interferon Type II Intracranial Neoplasms Intravenous Location Maintenance Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Methods Modeling Mus Neoadjuvant Therapy Outcome PD-1 blockade Pathway interactions Patients Pharmacology Population Pre-Clinical Model Publications Publishing Randomized Recurrence Refractory Regulatory Pathway Resistance Science Site Solid Neoplasm Suppressor-Effector T-Lymphocytes T-Cell Activation T-Lymphocyte Therapeutic Toxic effect Transcend Transforming Growth Factor beta Tumor Antigens Tumor Immunity Tumor-associated macrophages Variant anti-PD-1 anti-PD1 therapy beta Chain Antigen T Cell Receptor cancer therapy checkpoint inhibition clinical application clinical development clinically relevant combinatorial cytotoxic draining lymph node effector T cell experience immune activation immune checkpoint blockade immunoregulation medulloblastoma molecular subtypes monocyte novel prevent programmed cell death ligand 1 programmed cell death protein 1 recruit resistance mechanism therapy resistant tool tumor tumor heterogeneity tumor microenvironment

项目摘要

PROJECT SUMMARY AND ABSTRACT Harnessing the immune system for the treatment of cancer through PD-1 checkpoint inhibitor has shown considerable promise in a number of solid tumors. Recently, the use of neoadjuvant PD-1 checkpoint blockade demonstrated prolonged overall survival in a randomized study of patients with recurrent glioblastoma. However, outcomes remain poor for these patients, with an observed median survival of 13.2 months and most patients succumbing to disease progression. Our group has found a novel way to overcome treatment resistance to adjuvant αPD-1 monotherapy by employing concomitant transfer of bone marrow-derived hematopoietic stem and progenitor cells (HSC) with PD-1 checkpoint inhibition in preclinical models of CNS malignancies. We have demonstrated that HSCs co-transferred with immunotherapy significantly increases accumulation and significant activation of tumor-reactive T cells and tumor-associated dendritic cells (DC) within malignant glioma and medulloblastoma. Here we will dissect the mechanisms by which HSCs simultaneously modulate multiple pathways within the tumor microenvironment to potentiate anti-tumor immunity in preclinical models of cortical high grade glioma (KR158B) and Group 3 molecular subtype medulloblastoma (NSC). We have recently published that HSC + αPD-1 overcomes treatment resistance to αPD-1 in both f high grade glioma and cerebellar medulloblastoma which are tumors with distinct genetic backgrounds and anatomic location. We believe that this therapy has unifying mechanisms that transcends the differences in the types of malignant brain tumors and their anatomical location in these orthotopic models. The major impact of our study is that we have discovered a clinically applicable method of overcoming treatment resistance to αPD-1 in multiple refractory brain tumors. Importantly, we believe that combinatorial HSC + αPD-1 dramatically reduces modulatory pathways within brain tumors while displacing endogenous suppressor cells. This leads to the observed subsequent increases in anti- tumor T cell activation within the tumor microenvironment. The characterization and development of a singular intravenously-delivered immunotherapeutic that can target multiple immune regulatory pathways within several distinct brain tumors is highly significant and clinically relevant. Our HYPOTHESIS is that HSCs overcome treatment resistance to PD-1 checkpoint blockade through altering the cell fate differentiation of multi-lineage cellular compartments within the tumor microenvironment. Towards this end, the AIMS of this project are to: AIM 1. Determine the mechanism by which HSC + αPD-1 potentiate immune activation within the tumor microenvironment; AIM 2. Identify pathways that allow escape from HSC + αPD-1 therapy; AIM 3. Determine strategies to enhance the efficacy of HSC + αPD-1.

项目概要和摘要研究表明，通过 PD-1 检查点抑制剂利用免疫系统治疗癌症最近，使用PD-1检查点阻断新辅助疗法在许多实体瘤中具有相当大的前景。一项针对复发性胶质母细胞瘤患者的随机研究表明，总体生存期延长了。这些患者的结果仍然很差，观察到的中位生存期为 13.2 个月，大多数患者我们的小组找到了一种克服治疗耐药性的新方法。通过同时移植骨髓造血干细胞辅助 αPD-1 单一疗法 CNS 恶性肿瘤临床前模型中具有 PD-1 检查点抑制作用的祖细胞 (HSC)。与免疫疗法共同转移的 HSC 显着增加积累，并且显着恶性神经胶质瘤内肿瘤反应性 T 细胞和肿瘤相关树突状细胞 (DC) 的激活在这里，我们将剖析 HSC 同时调节多个的机制。肿瘤微环境中增强皮质临床前模型抗肿瘤免疫的途径我们最近发现了高级别胶质瘤 (KR158B) 和第 3 组分子亚型髓母细胞瘤 (NSC)。发表 HSC + αPD-1 克服了高级胶质瘤和小脑瘤对 αPD-1 的治疗耐药性髓母细胞瘤是具有不同遗传背景和解剖位置的肿瘤。治疗具有超越恶性脑肿瘤类型差异的统一机制我们研究的主要影响是我们发现了它们在这些原位模型中的解剖位置。一种克服多种难治性脑肿瘤对 αPD-1 治疗耐药性的临床适用方法。重要的是，我们相信 HSC + αPD-1 的组合可显着减少大脑内的调节通路肿瘤同时取代内源性抑制细胞，这导致观察到的抗-细胞随后增加。肿瘤微环境中肿瘤 T 细胞的活化。静脉注射免疫治疗，可以针对多种免疫调节途径我们的假设是 HSC 能够克服不同的脑肿瘤。通过改变多谱系的细胞命运分化来抵抗 PD-1 检查点阻断治疗为此，该项目的目标是： AIM 1. 确定HSC + αPD-1增强肿瘤内免疫激活的机制微环境；AIM 2. 确定逃离 HSC + αPD-1 治疗的途径；AIM 3. 确定增强 HSC + αPD-1 功效的策略。