Targeting the Premetastatic Niche by Antiangiogenic Immunotherapy

通过抗血管生成免疫疗法靶向转移前生态位

基本信息

批准号：
9020741
负责人：
Maciej Michal Markiewski
金额：
$ 35万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020741
关键词：
Adverse effects Affect Angiogenesis Inhibitors Biology Blood Vessels Breast Cancer Model Breast Carcinoma C5a anaphylatoxin receptor CD8B1 gene Cancer Etiology Cancer Model Cessation of life Chemotherapy-Oncologic Procedure Clinic Complement Complement 5a Complement Activation Data FDA approved Failure Goals Growth Human Immune response Immunization Immunosuppressive Agents Immunotherapy Infiltration Intervention Lesion Listeria Listeria monocytogenes Liver Lung Lung Neoplasms Lymphoid Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Modeling Mus Myelogenous Neoplasm Metastasis Neoplasms in Vascular Tissue Organ Pathway interactions Patients Pericytes Pharmaceutical Preparations Pregnancy Primary Neoplasm Publishing Receptor Inhibition Research Resistance Role Signal Transduction Staging Suppressor-Effector T-Lymphocytes T cell response Toxic effect Transforming Growth Factor beta Receptors Vaccines Vascular Permeabilities Work Wound Healing angiogenesis base clinically relevant comparative efficacy density design in vivo inhibitor/antagonist lung metastatic neoplastic cell new therapeutic target peripheral blood prevent public health relevance receptor research study resistance mechanism targeted treatment vascular contributions

项目摘要

DESCRIPTION (provided by applicant): This project seeks to provide the proof-of-concept for antiangiogenic immunotherapy targeting the premetastatic niche. We have found that complement C5a receptor (C5aR)-dependent angiogenesis begins in the lungs prior to the arrival of tumor cells and facilitates metastases; thus, this angiogenesis contributes to the premetastatic niche. These findings broaden our understanding of cancer-associated angiogenesis, since it is currently thought that angiogenesis begins in metastasis-targeted organs after metastases are present, facilitating the progression of dormant lesions to rapidly growing metastatic tumors. Leveraging our expertise in Listeria monocytogenes-based therapies and complement biology, we propose to use a combination of Listeria-based antiangiogenic vaccines and the inhibition of complement C5a receptor (C5aR) to stop premetastatic angiogenesis and metastases. This project is based on our recently published work demonstrating that inhibition of C5aR can prevent lung and liver metastases by enhancing antitumor CD8+ T-cell responses in these organs. The mechanisms to explain these beneficial effects include the complement- dependent reduction of lung and liver infiltration by myeloid-derived suppressor cells (MDSC), which are often blamed for the failure of various anticancer immunotherapies in the clinic. Therefore, we hypothesize that targeting MDSC through C5aR inhibition will synergize with and potentiate the actions of Listeria vaccines targeting premetastatic angiogenesis. Through these studies, we will identify the mechanisms regulating vascular alterations in the premetastatic niche that facilitate metastasis and design antiangiogenic therapy to target this niche. This strategy has the potential to prevent, delay, or reduce the metastases to vital organs that are responsible for 90% of cancer deaths. We will design an anticancer immunotherapy with minimal adverse effects, in contrast to the currently used toxic chemotherapy regimens. We anticipate that this active antiangiogenic immunization will induce a long-lasting immune response to the pathological vasculature, eliminating or reducing the need for frequent or prolonged administration of C5aR inhibitor and vaccines. Toward the goals of this application, we propose two well-integrated aims that will inform each other: (1) to identify the mechanisms regulating vascular alterations in the premetastatic niche, and (2) to compare the efficacy of the combined immunotherapy involving C5aR inhibition and Listeria antiangiogenic vaccines to monotherapy involving only one of these interventions and to the currently approved antiangiogenic therapies; and to identify the mechanisms of the synergistic action of C5aR inhibition and antiangiogenic vaccines. These aims will be achieved through in vivo studies in clinically relevant models of cancer.

描述（由适用提供）：该项目旨在为针对替代前转移壁球的抗血管生成免疫疗法提供概念验证。我们发现，补体C5A接收器（C5AR）依赖性血管生成在肺部到来之前始于肺部，并促进转移。因此，这种血管生成有助于前转移性小众。这些发现扩大了我们对与癌症相关的血管生成的理解，因为目前认为存在转移后，血管生成始于转移的靶向器官，这支持了休眠病变对快速生长的转移性肿瘤的发展。利用我们在基于单核细胞增生李斯特菌的疗法和补体生物学方面的专业知识，我们建议将基于李斯特菌的抗血管生成疫苗和抑制补体C5A受体（C5AR）结合使用，以阻止前抗激活血管生成和转移酶。该项目基于我们最近发表的工作，表明C5AR的抑制可以通过增强这些器官中的抗肿瘤CD8+ T细胞反应来防止肺和肝转移。解释这些有益效果的机制包括依赖于髓样衍生的抑制细胞（MDSC）的肺和肝脏浸润的补体降低，这些抑制细胞（MDSC）通常会因诊所中各种抗癌免疫疗法的失败而造成毛骨状。因此，我们假设通过C5AR抑制靶向MDSC将与靶向前转移血管生成的李斯特菌疫苗的作用协同作用。通过这些研究，我们将确定促进转移和设计抗血管生成疗法以靶向这种利基的机制。该策略有可能预防，延迟或减少转移到造成90％癌症死亡的重要器官。与当前使用的有毒化疗方案相比，我们将设计一种具有最小不良反应的抗癌免疫疗法。我们预计，这种活跃的抗血管生成免疫抑制将对病理脉管系统产生长期的免疫响应，消除或减少经常或长时间给药C5AR抑制剂和疫苗的需求。达到该应用程序的目标，我们提出了两个良好的目标，可以互相告知：（1）确定调节前播种细分市场中血管变化的机制，以及（2）比较涉及C5AR抑制和listeria抗合性疫苗的合并免疫疗法的效率，该疗法仅带有抗生物学性疫苗，这些疫苗仅带有这些间隔，并将其属于这些间隔效果。并确定C5AR抑制和抗血管生成疫苗的协同作用的机制。这些目标将通过在临床相关的癌症模型中的体内研究来实现。