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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.

总结