Reprogramming the tumor microenvironment to improve immunotherapy of glioblastoma by co-targeting VEGF and Ang2

通过共同靶向 VEGF 和 Ang2 重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗

基本信息

批准号：
10394968
负责人：
Dai Fukumura
金额：
$ 40.34万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-05-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394968
关键词：
Adverse effects Adverse event Angiopoietin-2 Antibodies Antigen-Presenting Cells Autoimmune Bispecific Antibodies Blood Vessels Brain Neoplasms CD8-Positive T-Lymphocytes Cell Adhesion Molecules Cell Communication Cells Cervical Clinical Research Clinical Trials Design Combined Modality Therapy Complex Cytolysis Cytotoxic T-Lymphocytes Data Development Drug Delivery Systems Edema Endothelial Cells FDA approved Failure Glioblastoma Glioma Hemorrhage Hypoxia Imaging Techniques Immune Immunoglobulin G Immunohistochemistry Immunologic Surveillance Immunosuppression Immunotherapy Impairment Infiltration Inflammation Inflammatory Response Literature Long-Term Survivors Lymphocyte Function Malignant neoplasm of lung Measures Mediating Memory Mus Myeloid Cells Operative Surgical Procedures Organ Patients Perfusion Peripheral Phase III Clinical Trials Phenotype Pilot Projects Proliferating Publishing Quality of life Radiation Reaction Regulatory T-Lymphocyte Resistance Risk Spleen Surgical Models T-Lymphocyte Testing Toxic effect Treatment Efficacy Tumor Antigens Tumor Burden Tumor Immunity Up-Regulation Vascular Endothelial Growth Factors anti-PD-1 anti-PD1 therapy antibody test antibody-dependent cell cytotoxicity base bevacizumab cancer cell cell killing comorbidity cytokine dosage immune checkpoint blockers improved improved outcome in vivo in vivo imaging insight intravital imaging lymph nodes lymphocyte trafficking macrophage melanoma neoantigens neoplastic cell novel strategies novel therapeutics preclinical study receptor repaired resistance mechanism response standard of care trafficking tumor tumor microenvironment tumor-immune system interactions vascular abnormality

项目摘要

SUMMARY Glioblastoma (GBM) is a universally fatal brain tumor. Immune checkpoint blockers (ICBs), such as anti- programmed cell death-1 protein (aPD1), alone or in combination with bevacizumab - an anti-vascular endothelial growth factor antibody (aVEGF), failed to improve survival in phase III clinical trials in GBM. This failure is, in part, due to the formidable barriers that the GBM tumor microenvironment (TME) creates. First, GBM tumor cells are highly proliferative and invasive with low neoantigen load, and thus, can easily evade immune surveillance. Second, GBM vessels are abnormal, and thus, they create a leaky, hypoxic and edematous TME and limit the delivery of drugs and the access of antitumor immune cells such as cytotoxic T lymphocytes (CTLs) into the tumor resulting in a cold CTL-excluded TME. Moreover, limited number of CTLs that accrue within GBM TME are dysfunctional. In contrast, pro-tumor immune cells such as regulatory T cells (Tregs) and “M2-like” macrophages preferentially accumulate in GBM. Unlike CTLs, Tregs and “M2-like” macrophages do not require intact vessels for trafficking to the tumor and thrive and proliferate in the GBM TME. Third, our pilot studies indicate that aPD1 aggravates vascular abnormalities and inflammatory responses in GBM, causing toxicities. Collectively, these features give rise to a strongly immunosuppressive TME in GBM that resists both the standard of care (SoC) and immunotherapy. Our preclinical and clinical studies and those of others indicate that angiopoietin-2 (Ang-2) can shorten the duration of aVEGF-induced vascular normalization. Thus, we hypothesize that normalizing tumor vasculature by co-targeting angiopoietin-2 (Ang-2) and aVEGF (abbreviated as aA2V) can both overcome resistance to aPD1 and reduce toxicities in patients with GBM. We will test if aA2V+aPD1 can durably normalize tumor vessels and improve their function. At cellular level, we will test if aA2V+aPD1 can repair the dysfunctional endothelial cells to express adhesion molecules, which are required for CTL cell trafficking, convert them to non-canonical antigen presenting cells to present tumor antigens to CTLs, and collectively result in improved CTL infiltration and function (Aim 1). We will further determine the involvement of antibody- dependent cell cytotoxicity (ADCC) in aPD1-induced adverse events and their alleviation by aA2V (Aim 2). Finally, we will use our newly developed surgical model that faithfully recapitulates GBM therapy in mice including SoC (surgery and chemo radiation) to test whether combining SoC with aA2V+aPD1 can promote durable responses (longer survival and memory responses) (Aim 3). Our findings will provide unprecedented insights into the mechanisms of resistance to immunotherapy in GBM, establish a novel strategy to overcome this resistance while abrogating putative adverse effects, and directly inform the design of clinical trials of GBM patients with combination aA2V+aPD1 therapy and SoC.

概括胶质母细胞瘤（GBM）是一种普遍致命的脑肿瘤。免疫检查点阻滞剂（ICB），例如抗程序性细胞死亡-1蛋白（APD1），单独或与贝伐单抗联合使用 - 抗血管内皮生长因子抗体（AVEGF）未能改善GBM III期临床试验的生存率。这个失败是在部分是由于GBM肿瘤微环境（TME）产生的强大障碍。首先，GBM肿瘤细胞具有低新抗原负荷的高度增殖和侵入性，因此很容易逃避免疫监测。其次，GBM血管异常，因此，它们会产生漏水，低氧和水肿的TME，并限制药物的递送以及抗抗毒物免疫细胞（例如细胞毒性T淋巴细胞（CTL））进入肿瘤导致冷CTL排除的TME。此外，GBM TME中产生的CTL数量有限为功能失调。相反，促肿瘤免疫细胞（例如调节T细胞（Treg）和“ M2样”巨噬细胞优先积聚在GBM中。与CTL不同，Tregs和“ M2 like”巨噬细胞不需要完整的视频用于贩运肿瘤，并在GBM TME中繁殖和增殖。第三，我们的试点研究表明APD1 加剧了GBM的血管异常和炎症反应，引起毒性。总的来说，这些特征在GBM中引起了强烈的免疫抑制性TME，既抗拒护理标准（SOC）和免疫疗法。我们的临床前和临床研究以及其他研究表明Angiopietin-2（Ang-2）可以缩短了AVEGF诱导的血管归一化的持续时间。那我们假设肿瘤归一化通过共同靶向Angiopietin-2（ANG-2）和AVEGF（缩写为AA2V）的脉管系统都可以克服对APD1的抗性并降低GBM患者的毒性。我们将测试AA2V+APD1是否可以使肿瘤血管归一化并改善其功能。在蜂窝级别，我们将测试AA2V+APD1是否可以修复功能失调的内皮细胞表达CTL细胞运输所需的粘附分子，转化它们可至非典型抗原呈现细胞，以将肿瘤抗原呈现给CTL，并统称导致改善了CTL浸润和功能（AIM 1）。我们将进一步确定抗体的参与 APD1诱导的不良事件中的依赖性细胞毒性（ADCC）及其通过AA2V减轻（AIM 2）。最后，我们将使用新开发的手术模型，忠实地概括了小鼠的GBM治疗包括SOC（手术和化学辐射），以测试将SOC与AA2V+APD1合并是否可以促进耐用的响应（生存和记忆反应较长）（AIM 3）。我们的发现将提供前所未有的洞悉GBM中对免疫疗法的抵抗机制，建立了一种新的策略来克服这一点抗性同时废除了推定的不良反应，并直接告知GBM临床试验的设计组合AA2V+APD1治疗和SOC的患者。