Tumor microenvironment: Impact on T cell tumor-targeting, activation and survival

肿瘤微环境：对 T 细胞肿瘤靶向、激活和存活的影响

基本信息

批准号：
8631072
负责人：
Ronald George Blasberg
金额：
$ 50.35万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-09 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631072
关键词：
Acidosis Affect Animal Model Animals Biological Assay Blood flow Bone neoplasms Cancer Patient Cell Therapy Cell physiology Cells Characteristics Clinic Clinical Research Data Drug Design Glutamate Carboxypeptidase II Human Hypoxia Image Imaging Techniques Immune response Immune system Immunocompetent Immunotherapy Interdisciplinary Study Intervention Lung Neoplasms Magnetic Resonance Spectroscopy Malignant neoplasm of prostate Measurement Measures Mediating Metastatic Lesion Modality Modeling Monitor Patients Positron-Emission Tomography Production Prostate Records Reporter Reporter Genes Research Research Infrastructure Signal Transduction Stromal Neoplasm System T cell therapy T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Transforming Growth Factors Translating Tumor-Derived cancer stem cell carbonate dehydratase chimeric antigen receptor cytokine cytotoxicity experience extracellular improved inhibitor/antagonist lactate dehydrogenase A multimodality novel response stem cell therapy trafficking treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): An abnormal tumor microenvironment can impair T cell function and limit the immune response. Tumor- derived lactate and an acidic microenvironment, as well as tumor/stromal secretion of TGF¿ can independently and synergistically suppress T cell proliferation, cytokine production and cytotoxicity. We propose to alter components of the tumor microenvironment (pHe, lactate and TGF¿) and assess these effects on PSMA chimeric antigen receptor (CAR) specific T cell therapy in two highly aggressive, immunocompetent animal models of prostate cancer with orthotopic, lung and bone tumor growth. Our central theme and hypothesis is that a markedly abnormal tumor microenvironment affects T cell tumor-targeting and survival, as well as T cell activation, proliferation and effector-function, and that these T cell functions can be monitored using novel dual reporter systems. A constitutive-reporter will be used for imaging T cell trafficking, tumor targeting and survival, and inducible-reporter systems will concurrently image and assess T cell function. One inducible reporter will monitor T cell activation mediated through a PSMA- specific CAR; the other will monitor TGF¿-signaling in T cells. The effects of genetically induced abnormalities in the tumor microenvironment (low pHe, high lactate and high TGF¿) on T cell trafficking and function will be assessed using multimodality imaging techniques. The status of the tumor microenvironment will be assessed repeatedly in the same animal using MRIS to measure pHe and lactate, and microPET to assess tumor hypoxia during tumor growth and during adoptive T cell therapy. Additional ex vivo immunohistochemical cell assays will independently assess the tumor microenvironment and confirm T cell status. We also expect that "normalization" of different components of the tumor microenvironment (pHe, lactate and TGF¿) using pharmacological intervention will significantly enhance T cell therapy; therefore, we have included therapeutic sub-aims to test this hypothesis. The relevance and impact of these studies are that: 1) Lactate, pHe, and TGF¿ levels in the tumor microenvironment are frequently abnormal, particularly in more aggressive tumors, and are associated with a reduced immune response. 2) Importantly, there exist specific treatment modalities to "normalize" these components, and they will be investigated. 3) Many of the imaging strategies developed and used in this project (e.g., MRSI to measure pHe and lactate) could be translated to clinical studies, where monitoring T cell trafficking and function can be monitored in patients using human reporter genes and PET imaging, and where adoptive T cell treatment strategies could be more fully evaluated.

描述（由申请人提供）：异常的肿瘤微环境会损害 T 细胞功能并限制肿瘤衍生的乳酸和酸性微环境以及 TGF 的肿瘤/基质分泌。可以独立且协同地抑制 T 细胞增殖、细胞因子产生和细胞毒性。我们建议改变肿瘤微环境的成分（pHe、乳酸和 TGF¿），并评估这些对 PSMA 嵌合抗原受体 (CAR) 特异性 T 细胞疗法的影响。我们的中心主题和假设是，明显异常的肿瘤微环境会影响 T 细胞的肿瘤靶向和存活，以及 T 细胞。激活、增殖和效应功能，并且可以使用新型双报告系统监测这些 T 细胞功能，组成型报告系统将用于成像 T 细胞运输、肿瘤靶向和存活，诱导型报告系统将同时成像和检测。评估 T 细胞功能。一种诱导型报告基因将监测通过 PSMA 特异性 CAR 介导的 T 细胞激活；另一种将监测 TGF¿ - T 细胞中的信号传导。将使用多模态成像技术评估肿瘤微环境中遗传诱导的异常（低 pHe、高乳酸和高 TGF¿）对 T 细胞运输和功能的影响。在同一动物中重复使用 MRI 测量 pHe 和乳酸，并使用 microPET 评估肿瘤生长期间和过继性 T 细胞治疗期间的肿瘤缺氧情况。另外的离体免疫组织化学细胞测定将独立评估肿瘤。我们还期望使用药物干预使肿瘤微环境的不同成分（pHe、乳酸和 TGF¿）“正常化”将显着增强 T 细胞治疗；因此，我们纳入了测试的治疗子目标；这些研究的相关性和影响是：1) 乳酸、pHe 和 TGF¿肿瘤微环境中的水平经常异常，特别是在更具侵袭性的肿瘤中，并且与免疫反应降低有关。 2) 重要的是，存在使这些成分“正常化”的特定治疗方式，并且将对其进行研究。该项目中开发和使用的成像策略（例如，测量 pHe 和乳酸的 MRSI）可以转化为临床研究，其中可以使用人类报告基因和 PET 成像来监测患者的 T 细胞运输和功能，并且过继 T可以更全面地评估细胞治疗策略。