Novel combined immunotherapeutic strategies for glioma: using pet dogs as a large animal spontaneous model

胶质瘤联合免疫治疗新策略：使用宠物狗作为大型动物自发模型

基本信息

批准号：
9449905
负责人：
Grace Elizabeth Pluhar
金额：
$ 163.28万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449905
关键词：
Address Adenoviruses Adverse effects Animals Antigen Presentation Astrocytoma Autologous Boston Brain Neoplasms CD 200 Canis familiaris Chromosome abnormality Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Classification Clinic Clinical Clinical Trials Combined Modality Therapy Complex Contralateral Data Development Disease Excision FDA approved FLT3LG gene FRAP1 gene Genes Glioblastoma Glioma Histologic Human IGF1R gene Immune Immune checkpoint inhibitor Immune response Immunologic Memory Immunologic Surveillance Immunologics Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Implant Interferon Type II Long-Term Survivors Lymphocyte Malignant Neoplasms Malignant neoplasm of brain Mediating Michigan Minnesota Modeling Mus Myelogenous Natural Killer Cells Neoplasms Operative Surgical Procedures Outcome PDCD1LG1 gene Patients Peptides Phase Pilot Projects Prevalence Primary Brain Neoplasms Primary Neoplasm Proteins RB1 gene RNA Radiation Rattus Recruitment Activity Recurrence Recurrent tumor Refractory Regulatory T-Lymphocyte Reporting Research Personnel Residual Tumors Risk Rodent Model Safety Solid Neoplasm Source Suppressor-Effector T-Lymphocytes System TK Gene Testing Therapeutic Therapeutic Intervention Time Toxic effect Translating Translational Research Translations Treatment Efficacy Treatment outcome Tumor Antigens Tumor Cell Derivative Vaccine Tumor Immunity Universities Vaccines World Health Organization adenoviral-mediated arm cancer immunotherapy cancer therapy cell type checkpoint therapy chemotherapy comparative genomics cytokine cytotoxic dog genome gene therapy immune checkpoint immune checkpoint blockade improved inhibitor/antagonist innovation lymph nodes macrophage melanoma migration neoplastic cell novel novel therapeutics outcome forecast response scale up standard of care targeted treatment temozolomide tumor tumor microenvironment tumor progression uptake

项目摘要

There is a growing body of evidence that spontaneous cancers in dogs represent attractive translational models. In the field of immunotherapy, dogs offer an innovative model for translational research, as they present many of the challenges faced in “scaling up” therapeutic systems dependent on complex interactions between multiple cell types yet under more controlled settings. They also allow for long-term assessment of efficacy and toxicities. Canine clinical trials offer unique access to a rich source of spontaneously occurring, genetically and immunologically diverse cancers with the benefits of reduced time, expense, and regulatory hurdles of a human trial. The similarities between canine and human cancers are increasingly being realized. The publicly available canine genome has propelled comparative genomics studies that have shown significant homology between dogs and humans for recognized cancer-associated genes including MET, IGF1R, mTOR, and KIT. Not surprisingly, cytogenetic abnormalities that define human cancers, i.e. BCR-Abl translocations in chronic myelogenous leukemia and RB1 deletions in chronic lymphocytic leukemia have been found in comparable canine cancers. Intracranial neoplasia occurs frequently in dogs with a reported prevalence from 0.15 to 4.5% compared to 18.2 cases per 100,000 human. Astrocytoma or glioma account for 20-36% of primary brain tumors in dogs and 25% in humans. Brachycephalic breeds such as Boxers, French and English bulldogs, and Boston terriers have a significantly increased risk of developing gliomas. Primary canine brain tumors have similar histologic classification as those reported by the World Health Organization for human brain tumors. Similar to that in humans, the prognosis for dogs with brain tumors in general is poor regardless of therapeutic intervention. However, much less is known about canine glioma treatment outcomes because only a small number of studies with few dogs have been reported. There is little information about median survival time for dogs with glioma that received any type of treatment, but estimates of days to 2 or 3 months are often given to owners. The clinical similarities between dogs and humans suggest that dogs may represent an outstanding model for testing targeted therapies; both dogs and humans might benefit from these studies. Herein, we are proposing a multi-pronged immunotherapeutic approach to improve efficacy and survival times. We hypothesize that combination immunotherapy in a canine glioma model will enhance efficacy and accelerate successful translation into phase I human trials for GBM. The objective is to use pet dogs with spontaneous GBM to demonstrate the safety and efficacy of combination immunotherapy. We propose two Specific Aims: 1. Determine the safety and efficacy of immune checkpoint blockade in spontaneous canine GBM in combination with standard of care, and 2. Assess the efficacy of immune-mediated gene therapy in combination with CD200 blockade to enhance anti-glioma immunotherapy. !

越来越多的证据表明狗中的赞助商代表着有吸引力的翻译型号。在免疫疗法领域，狗为翻译研究提供了创新的模型介绍了“扩展”治疗系统中所面临的许多挑战，取决于复杂的相互作用在多种单元类型之间，但在更受控的设置下。他们还允许对功效和毒性。犬临床试验可独特地访问丰富的赞助来源，一般和免疫学上多样的癌症，带来了减少时间，费用和监管的好处人类审判的障碍。犬和人类癌症之间的相似之处正在越来越多地实现。公开可用的犬基因组推动了比较基因组学研究，这些研究表明狗与人之间的同源性，用于公认的癌症相关基因，包括Met，IGF1R，MTOR，和套件。毫不奇怪，定义人类癌的细胞遗传学异常，即BCR-ABL易位在慢性淋巴细胞性白血病中的慢性骨髓性白血病和RB1缺失已在可比较的犬癌。颅内肿瘤经常发生在据报道患病率的狗中 0.15％至4.5％，而每100,000人为18.2例。星形细胞瘤或神经胶质瘤占20-36％狗的原发性脑肿瘤和人类的25％。 Brachycephalic品种，例如拳击手，法语和英语斗牛犬和波士顿梗犬患神经胶质瘤的风险显着增加。原发性犬大脑肿瘤的组织学分类与世界卫生组织报告的组织学分类类似脑肿瘤。与人类类似，无论如何，对脑肿瘤的狗的预后都很差理论干预。但是，关于犬神经胶质瘤治疗结果的了解少得多，因为仅报道了很少有狗的研究。关于中位数的信息很少接受任何类型治疗的神经胶质瘤的狗的生存时间，但估计为2或3个月经常给所有者。狗和人之间的临床相似性表明狗可能代表测试目标疗法的出色模型；狗和人类都可以从这些研究中受益。在此，我们提出了一种多支处理的免疫治疗方法，以提高效率和生存时间。我们假设犬神经瘤模型中的联合免疫疗法将提高效率，并且加速成功地转化为GBM的I期人类试验。目的是将宠物狗与赞助GBM以证明联合免疫疗法的安全性和效率。我们提出了两个具体目的：1。确定个人免疫障碍的安全性和效率犬GBM与标准的护理结合，2。评估免疫介导的基因的效率治疗与CD200封锁结合使用，以增强抗神经瘤免疫疗法。呢