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

越来越多的证据表明，狗的自发性癌症代表着诱人的翻译能力 模特们。在免疫治疗领域，狗为转化研究提供了一个创新的模型，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 在更受控制的设置下的多个细胞类型之间。它们还允许长期评估 功效和毒性。狗的临床试验提供了一个独特的途径，可以获得丰富的自发发生的来源， 基因和免疫多样化的癌症，其好处是减少时间、费用和监管 人体试验的障碍。人们越来越认识到犬癌和人类癌症之间的相似之处。 公开的犬类基因组推动了比较基因组学的研究，这些研究表明 狗和人之间识别的癌症相关基因的同源性，包括MET，IGF1R，mTOR， 还有基特。毫不奇怪，定义人类癌症的细胞遗传学异常，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缺失已在 类似的犬癌。颅内肿瘤经常发生在狗身上，据报道其患病率为 0.15%至4.5%，而每10万人中有18.2例。星形细胞瘤或胶质瘤占20%-36% 狗的原发性脑瘤和人类的25%。短头犬种，如拳击手、法国人和英国人 斗牛犬和波士顿梗犬患胶质瘤的风险显著增加。原发犬脑 肿瘤的组织学分类与世界卫生组织报告的人类肿瘤相似 脑瘤。与人类相似，患有脑瘤的狗的预后一般都很差。 进行治疗干预。然而，人们对犬脑胶质瘤的治疗结果知之甚少，因为 只有少数几只狗参与的研究被报道过。关于中位数的信息很少 接受任何类型治疗的神经胶质瘤狗的存活时间，但估计为数天至2或3个月 通常是送给车主的。狗和人类之间的临床相似性表明，狗可能代表着 一个测试靶向治疗的杰出模型；狗和人类都可能从这些研究中受益。 在此，我们提出了一种多管齐下的免疫治疗方法，以提高疗效和生存时间。 我们假设联合免疫疗法在犬脑胶质瘤模型中将提高疗效和 加速成功转化为GBM的I期人体试验。目标是将宠物狗与 自发性基底膜，以证明联合免疫治疗的安全性和有效性。我们建议两个 具体目标：1.确定自发性免疫检查点阻断的安全性和有效性 犬GBM与标准护理相结合；2.评估免疫介导基因的效果 联合应用CD200阻滞剂加强抗胶质瘤免疫治疗。

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.