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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。免疫检查点阻断剂 (ICB)，例如抗程序性细胞死亡 1 蛋白 (aPD1)，单独或与贝伐单抗（一种抗血管内皮细胞药物）联合使用生长因子抗体（aVEGF）在 GBM III 期临床试验中未能提高生存率。这次失败是在部分原因是 GBM 肿瘤微环境 (TME) 造成的巨大障碍。一、GBM肿瘤细胞具有高度增殖性和侵袭性，新抗原负荷低，因此可以轻松逃避免疫监视。其次，GBM 血管异常，因此会产生渗漏、缺氧和水肿的 TME，并限制药物输送和抗肿瘤免疫细胞（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 数量有限功能失调。相比之下，促肿瘤免疫细胞，例如调节性 T 细胞 (Treg) 和“M2 样”巨噬细胞优先积聚在GBM中。与 CTL 不同，Treg 和“M2 样”巨噬细胞不需要完整的血管运输到肿瘤并在 GBM TME 中茁壮成长和增殖。第三，我们的试点研究表明 aPD1 加重 GBM 中的血管异常和炎症反应，引起毒性。总的来说，这些这些特征会在 GBM 中产生强烈的免疫抑制性 TME，从而抵抗护理标准 (SoC) 和免疫疗法。我们以及其他人的临床前和临床研究表明，血管生成素-2 (Ang-2) 可以缩短aVEGF诱导的血管正常化的持续时间。因此，我们假设肿瘤正常化通过共同靶向血管生成素-2 (Ang-2) 和 aVEGF（缩写为 aA2V）的血管系统可以克服对 aPD1 具有抵抗力并减少 GBM 患者的毒性。我们将测试aA2V+aPD1是否可以持久使肿瘤血管正常化并改善其功能。在细胞水平上，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，将其转化为将它们传递给非经典抗原呈递细胞，将肿瘤抗原呈递给 CTL，并共同导致改善 CTL 浸润和功能（目标 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 的缓解（目标 2）。最后，我们将使用我们新开发的手术模型，忠实地重现小鼠 GBM 治疗包括SoC（手术和化疗放疗），测试SoC与aA2V+aPD1结合是否可以促进持久反应（更长的生存和记忆反应）（目标 3）。我们的研究结果将提供前所未有的深入了解 GBM 免疫治疗耐药机制，建立克服这一问题的新策略耐药性，同时消除假定的不良反应，并直接为 GBM 临床试验的设计提供信息接受 aA2V+aPD1 联合治疗和 SoC 的患者。