Understanding and enhancing mechanisms of priming in cancer immunotherapy

了解和增强癌症免疫治疗的启动机制

基本信息

批准号：
8113306
负责人：
Grace Elizabeth Pluhar
金额：
$ 11.33万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113306
关键词：
Adjuvant Age Animal Model Animals Antibodies Antibody Formation Antigens Autologous Tumor Cell B-Lymphocytes Biological Assay Biological Markers Brain Brain Neoplasms CD8B1 gene Cancer Etiology Cancer Vaccines Canis familiaris Cell Culture Techniques Cells Cessation of life Clinical Clinical Trials Clinical Trials Design Clonality Cultured Tumor Cells Cytoplasmic Granules Cytotoxic T-Lymphocyte Analysis Cytotoxic T-Lymphocytes Data Dendritic Cells Dose Exhibits Flow Cytometry Frequencies Genetic Glioma Goals Heterogeneity Human Hypoxia Hypoxia Inducible Factor Immune response Immune system Immunologic Monitoring Immunologics Immunotherapy Interleukin-2 Knowledge Magnetic Resonance Imaging Malignant Glioma Malignant neoplasm of brain Modeling Molecular Target Mus Operative Surgical Procedures Outcome Oxygen Oxygen measurement, partial pressure, arterial Patients Phenotype Physiologic pulse Physiological Postoperative Period Production Progression-Free Survivals Property Proteins Randomized Recruitment Activity Relative (related person)Residual state Safety Site Source Steroids Structure T cell response T-Lymphocyte TNF gene Testing Therapeutic Toxic effect Tumor Antigens Tumor Burden Tumor-Derived Vaccinated Vaccination Vaccine Production Vaccines Validation Virus Diseases base cancer immunotherapy cancer stem cell chemotherapy clinical efficacy clinically relevant cohort cytokine cytotoxic epidermal growth factor receptor VIII experience human data immunogenic immunogenicity improved innovation killings melanoma mouse model neoplastic cell novel novel vaccines peripheral blood preclinical evaluation public health relevance research study response temozolomide tissue culture trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): Malignant brain tumors are the leading cause of cancer-related death in people under age 35. Novel therapies that selectively target residual migratory glioma cells after surgery are urgently needed. Therapies that will be effective against these extremely heterogeneous tumors should have broad molecular targets. Immunotherapy using autologous tumor cell lysate vaccines targeting multiple tumor antigens is a promising approach being tested in numerous clinical trials. However, complete tumor regression is rarely achieved. The effect of cell culture conditions during vaccine production on the immune response and clinical outcome is poorly understood. Moreover, although tumor-reactive T cells may be correlated to prolonged survival in select patients, the functional heterogeneity of responding T cells and their relation to antibody response and clinical outcome is inadequately defined. We discovered that the oxygen concentration used to culture tumor cells during vaccine production flips an immunologic switch, dictating whether cytotoxic T lymphocytes (CTL) or antibody production dominate in the resulting immune response. Glioma cells grown in physiologic brain oxygen (5% O2) have enhanced adjuvant properties, are enriched for a cancer stem cell phenotype, and increase expression of known immunogenic glioma antigens relative to cells grown in the conventional oxygen level (20% O2). Furthermore, glioma-bearing mice vaccinated with glioma lysates prepared from 5% O2 cultures mixed with CpG oligodeoxynucleotides (ODN) as an adjuvant exhibit a three- fold increase in tumor infiltrating T cells and significantly increased survival relative to mice vaccinated with lysates from 20% O2 cultures. We propose to elucidate the effect that oxygen concentration used during vaccine production has on the immune response and clinical response in an innovative large animal model of glioma. We have established that pet dogs with spontaneous gliomas represent an outstanding animal model in which surgery, steroids, and postoperative chemotherapy can be given similar to human patients, lending great translational relevance to our findings. In specific aim 1, we will determine the difference in survival between dogs with glioma treated by surgery, chemotherapy, and vaccination with glioma lysate / CpG ODN prepared from cells cultured in 5% or 20% O2. Tumor burden and toxicity will be determined similar to human patients. In specific aim 2, the frequency of "polyfunctional" CTLs that secrete multiple effector cytokines and degranulate to kill tumor cells will be determined and correlated with tumor-reactive antibody response and survival. The deliverables of this study will be: i) new knowledge relating oxygen tension used in vaccine production to T and B cell responses and patient survival, ii) validation of immune monitoring assays useful in predicting which patients may respond to immunotherapy, iii) efficacy and safety data in the only useful large animal model of glioma in the world to justify accelerated clinical trial design in human glioma patients. PUBLIC HEALTH RELEVANCE: Glioma is an aggressive brain tumor that is very difficult to treat. Vaccines have been tested in glioma patients with suboptimal results. We have developed a novel vaccine with increased efficacy in mouse models. In this project we will determine if vaccination can increase the survival of pet dogs with glioma as a prelude to human clinical trials.

描述（由申请人提供）：35岁以下患者的恶性脑肿瘤是与癌症相关死亡的主要原因。迫切需要在手术后选择性地靶向残余迁移神经胶质瘤细胞的新型疗法。针对这些极端异质肿瘤有效的疗法应具有广泛的分子靶标。在许多临床试验中，使用靶向多种肿瘤抗原的自体肿瘤细胞裂解物疫苗的免疫疗法是一种有前途的方法。但是，很少实现完全的肿瘤回归。疫苗生产过程中细胞培养条件对免疫反应和临床结果的影响鲜为人知。此外，尽管肿瘤反应性T细胞可能与某些患者的延长生存率相关，但反应T细胞的功能异质性及其与抗体反应和临床结果的关系不足。我们发现，在疫苗生产过程中用于培养肿瘤细胞的氧浓度会翻转免疫学开关，这决定了细胞毒性T淋巴细胞（CTL）或抗体产生是否在产生的免疫反应中占主导地位。在生理脑氧中生长的胶质瘤细胞（5％O2）具有增强的辅助性能，富含癌症干细胞表型，并增加已知的免疫原性胶质瘤抗原相对于在常规氧气中生长的细胞的表达（20％O2）。此外，由5％O2培养物制备的伴有胶质瘤裂解物与CpG寡脱氧核苷酸（ODN）作为辅助物混合的伴有胶质瘤裂解物的含有胶质瘤的小鼠表现出肿瘤浸润T细胞的3倍升高，并且相对于从20％O2培养物中疫苗的小鼠疫苗的生存率显着增加，这显着增加了存活率。我们建议阐明疫苗生产过程中使用的氧气浓度对创新的胶质瘤大型动物模型的免疫反应和临床反应的作用。我们已经确定，具有自发神经胶质瘤的宠物犬代表了一种出色的动物模型，其中手术，类固醇和术后化学疗法可以与人类患者相似，与我们的发现相关。在特定的目标1中，我们将确定通过手术，化学疗法治疗的神经胶质瘤狗之间的生存差异和用裂解膜 / CpG ODN疫苗接种，该细胞从5％或20％O2中培养的细胞中制备。肿瘤负担和毒性将被确定与人类患者相似。在特定的目标2中，分泌多发性效应细胞因子并脱脂以杀死肿瘤细胞的“多功能” CTL的频率将与肿瘤反应性抗体反应和存活相关。这项研究的可交付成果将是：i）与T和B细胞反应和患者生存相关的氧张力，ii）验证免疫监测测定法，有助于预测哪些患者可能对免疫疗法的反应，iii III）在世界上唯一有用的大型动物模型中，可以证明ACCELASE ACCELECAL临床临床临床glioma in Human Glioma in Human Glioma in Human Glioma in Human Glioma in Human Glioma in Hull Glioma in Hull Glioma in Human Glioma in grog gliman in Human Glioma shorm Glioma唯一有用的安全数据。公共卫生相关性：神经胶质瘤是一种侵略性的脑肿瘤，很难治疗。疫苗已在胶质瘤患者的副作用效果下进行了测试。我们已经开发了一种新型疫苗，在小鼠模型中具有增加功效。在这个项目中，我们将确定疫苗接种是否可以增加伴有神经胶质瘤的宠物犬作为人类临床试验的前奏。