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）：恶性脑肿瘤是 35 岁以下人群癌症相关死亡的主要原因。迫切需要选择性针对手术后残留的迁移性神经胶质瘤细胞的新疗法。对这些极其异质性肿瘤有效的疗法应该具有广泛的分子靶点。使用针对多种肿瘤抗原的自体肿瘤细胞裂解物疫苗进行免疫治疗是一种有前途的方法，正在大量临床试验中进行测试。然而，很少实现肿瘤完全消退。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尚不清楚。此外，尽管肿瘤反应性 T 细胞可能与特定患者的生存期延长相关，但反应性 T 细胞的功能异质性及其与抗体反应和临床结果的关系尚未得到充分定义。我们发现，在疫苗生产过程中用于培养肿瘤细胞的氧气浓度会翻转免疫开关，决定细胞毒性 T 淋巴细胞 (CTL) 还是抗体生产在最终的免疫反应中占主导地位。相对于在常规氧水平 (20% O2) 中生长的细胞，在生理脑氧 (5% O2) 中生长的神经胶质瘤细胞具有增强的佐剂特性，富集癌症干细胞表型，并增加已知免疫原性神经胶质瘤抗原的表达。此外，与接种 20% 裂解物的小鼠相比，接种由 5% O2 培养物与 CpG 寡脱氧核苷酸 (ODN) 作为佐剂混合而成的神经胶质瘤裂解物的小鼠，其肿瘤浸润性 T 细胞增加了三倍，且存活率显着提高。 O2 培养物。我们建议阐明疫苗生产过程中使用的氧气浓度对创新的大型神经胶质瘤动物模型的免疫反应和临床反应的影响。我们已经确定，患有自发性神经胶质瘤的宠物狗代表了一种出色的动物模型，其中可以像人类患者一样进行手术、类固醇和术后化疗，这为我们的发现提供了巨大的转化相关性。在具体目标 1 中，我们将确定经过手术、化疗和接种由在 5% 或 20% O2 中培养的细胞制备的神经胶质瘤裂解物/CpG ODN 疫苗治疗的神经胶质瘤狗之间的生存差异。肿瘤负荷和毒性的测定与人类患者类似。在具体目标 2 中，将确定分泌多种效应细胞因子并脱颗粒杀死肿瘤细胞的“多功能”CTL 的频率，并将其与肿瘤反应性抗体反应和存活相关联。这项研究的成果将是：i) 将疫苗生产中使用的氧张力与 T 和 B 细胞反应以及患者生存相关的新知识，ii) 验证免疫监测测定，可用于预测哪些患者可能对免疫治疗产生反应，iii) 疗效和世界上唯一有用的大型神经胶质瘤动物模型的安全性数据证明了在人类神经胶质瘤患者中加速临床试验设计的合理性。公共卫生相关性：神经胶质瘤是一种非常难以治疗的侵袭性脑肿瘤。疫苗已在神经胶质瘤患者中进行了测试，但结果不佳。我们开发了一种新型疫苗，在小鼠模型中具有更高的功效。在这个项目中，我们将确定疫苗接种是否可以提高患有神经胶质瘤的宠物狗的存活率，作为人体临床试验的前奏。