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

• 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
• 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

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.

摘要 胶质母细胞瘤(GBM)是一种常见的致命性脑肿瘤。免疫检查点阻滞剂(ICB)，如抗- 程序性细胞死亡-1蛋白(APD1)，单独或与抗血管内皮细胞的贝伐单抗联合应用 生长因子抗体(AVEGF)在GBM的III期临床试验中未能提高存活率。这一故障是在 部分是由于GBM肿瘤微环境(TME)造成的强大屏障。首先，基底膜肿瘤细胞 具有高度增殖性和侵袭性，新抗原载量低，因此很容易逃脱免疫监视。 其次，基底膜血管是异常的，因此，它们会造成渗漏、缺氧和水肿性TME，并限制 药物的传递和抗肿瘤免疫细胞如细胞毒性T淋巴细胞(CTL)进入肿瘤的途径 导致冷的CTL排除的TME。此外，GBM TME内累积的有限数量的CTL是 功能失调。相比之下，促肿瘤免疫细胞，如调节性T细胞(Tregs)和类M2巨噬细胞 优先积累在GBM中。与CTL不同，Tregs和“M2样”巨噬细胞不需要完整的血管 贩运到肿瘤并在GBM TME中茁壮成长和增殖。第三，我们的初步研究表明，aPD1 加重GBM中的血管异常和炎症反应，导致毒副作用。总而言之，这些 特征导致GBM中的TME具有强烈的免疫抑制作用，可同时抵抗标准护理(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，血管生成素-2(Ang-2)可以 缩短血管内皮细胞生长因子诱导的血管正常化时间。因此，我们假设正常化的肿瘤 通过共同靶向血管生成素-2(Ang-2)和aVEGF(简称aA2V)的血管形成系统可以同时克服 GBM患者对aPD1的耐药性和减毒作用。我们将测试aA2V+aPD1是否能够持久 使肿瘤血管正常化，改善其功能。在细胞水平上，我们将测试aA2V+aPD1是否可以修复 功能障碍的内皮细胞表达CTL细胞运输所需的黏附分子，转化为 将肿瘤抗原递呈给CTL，并共同导致 改进了CTL的渗透和功能(目标1)。我们将进一步确定抗体是否参与- APD1诱导的不良事件中的依赖细胞细胞毒性(ADCC)以及aA2V的缓解作用(目标2)。 最后，我们将使用我们新开发的手术模型，它忠实地概括了小鼠的GBM治疗。 包括SoC(手术和化疗)，以测试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)。我们的发现将提供前所未有的 对GBM免疫治疗耐药机制的洞察，建立克服这一问题的新策略 在消除可能的不良反应的同时产生耐药性，并直接指导GBM临床试验的设计 AA2V+aPD1联合SOC组。