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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：
10252958
负责人：
Grace Elizabeth Pluhar
金额：
$ 54.08万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252958
关键词：
Address Adenoviruses Animals Antigen Presentation Astrocytoma Autologous Boston Brain Neoplasms CD 200 Canis familiaris Chemotherapy and/or radiation Chromosome abnormality Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Classification Clinic Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Complex Contralateral Data Development Disease Excision FDA approved FLT3 ligand FRAP1 gene Genes Glioblastoma Glioma Histologic Human IGF1R gene Immune Immune checkpoint inhibitor Immune response Immunologic Memory Immunologic Surveillance Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Implant Interferon Type II Long-Term Survivors Lymphocyte Malignant Neoplasms Malignant neoplasm of brain Mediating Michigan Minnesota Modeling Mus Myeloid-derived suppressor cells Natural Killer Cells Neoplasms Operative Surgical Procedures Outcome Patients Peptides Phase Pilot Projects Prevalence Primary Brain Neoplasms Primary Neoplasm Prognosis Proteins RB1 gene RNA Rattus Recurrence Recurrent tumor Refractory Regulatory T-Lymphocyte Reporting Research Personnel Residual Tumors Risk Rodent Model Safety Solid Neoplasm Source 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 Tumor-associated macrophages Universities World Health Organization adenoviral-mediated anti-tumor immune response arm cancer immunotherapy cancer therapy cell type checkpoint therapy comparative genomics cytokine cytotoxic dog genome draining lymph node efficacy evaluation gene therapy immune checkpoint immune checkpoint blockade improved inhibitor/antagonist innovation melanoma migration neoplastic cell novel novel therapeutics programmed cell death ligand 1 recruit response scale up side effect standard of care targeted treatment temozolomide translational model 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了有吸引力的转化