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，狗的自发性癌症代表着有吸引力的转化在免疫治疗领域，狗为转化研究提供了一种创新模型，因为它们提出了依赖于复杂相互作用的“扩大”治疗系统所面临的许多挑战它们还允许对多种细胞类型进行长期评估。犬类临床试验提供了获得自发产生的丰富来源的独特途径。遗传和免疫学上多样化的癌症，具有减少时间、费用和监管的优点人们越来越认识到犬类癌症和人类癌症之间的相似性。公开的犬类基因组推进剂引领了比较基因组学研究，这些研究表明了显着的意义狗和人类之间公认的癌症相关基因的同源性，包括 MET、IGF1R、mTOR、毫不奇怪，细胞遗传学异常定义了人类癌症，即 BCR-Abl 易位。慢性粒细胞白血病和慢性淋巴细胞白血病中的 RB1 缺失已被发现类似的犬类癌症经常发生在犬身上，据报道其患病率较高。 0.15% 至 4.5%，而星形细胞瘤或神经胶质瘤占每 100,000 人 18.2 例，占 20-36%。狗的原发性脑肿瘤，以及人类短头颅品种（如拳师犬、法国犬和英国犬）的原发性脑肿瘤。斗牛犬和波士顿梗犬患原发性犬脑胶质瘤的风险显着增加。肿瘤具有与世界卫生组织报告的人类肿瘤相似的组织学分类与人类相似，患有脑肿瘤的狗的预后通常很差。然而，人们对犬神经胶质瘤的治疗结果知之甚少，因为仅报道了少量狗的研究，有关中位数的信息很少。接受任何类型治疗的患有神经胶质瘤的狗的生存时间，但估计为几天到 2 或 3 个月狗和人类之间的临床相似性表明狗可能代表了主人。测试靶向疗法的杰出模型；狗和人类都可能从这些研究中受益。在此，我们提出一种多管齐下的免疫治疗方法来提高疗效和生存时间。我们率先在犬神经胶质瘤模型中联合免疫疗法将提高疗效并加速 GBM 的第一阶段人体试验的成功转化，目标是使用宠物狗。我们提出了两种自发性 GBM 来证明联合免疫疗法的安全性和有效性。具体目标： 1. 确定免疫检查点阻断在自发性疾病中的安全性和有效性犬 GBM 与标准护理相结合，以及 2. 评估免疫介导基因的功效与 CD200 阻断联合治疗可增强抗神经胶质瘤免疫治疗。！