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

• 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
• 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

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翻译 模型在免疫治疗领域，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“按比例放大”治疗系统所面临的许多挑战， 在多种细胞类型之间，但在更受控的设置下。它们还允许长期评估 疗效和毒性。犬临床试验提供了一个独特的途径，丰富的来源，自发发生， 基因和免疫多样性的癌症，具有减少时间、费用和调节的益处， 人体试验的障碍人们越来越认识到犬类癌症和人类癌症之间的相似性。 公开的犬基因组推动了比较基因组学研究， 狗和人类之间的同源性，用于识别癌症相关基因，包括MET、IGF 1 R、mTOR 和KIT。毫不奇怪，定义人类癌症的细胞遗传学异常，即BCR-Abl易位， 慢性髓细胞性白血病和慢性淋巴细胞性白血病中的RB 1缺失已在 类似的犬类癌症颅内肿瘤经常发生在狗与报告的患病率从 0.15 4.5%，而每10万人中有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%。短头犬种，如义和团犬、法国犬和英国犬 斗牛犬和波士顿梗类犬患神经胶质瘤的风险显著增加。原代犬脑 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， 治疗干预。然而，对犬神经胶质瘤治疗结果的了解要少得多， 只有少数研究报告了几只狗。关于中位数的信息很少。 接受任何类型治疗的胶质瘤犬的生存时间，但估计为数天至2或3个月 往往是给业主的。狗和人类之间的临床相似性表明，狗可能代表 这是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方法来提高疗效和生存时间。 我们假设在犬胶质瘤模型中联合免疫治疗将提高疗效， 加速成功转化为GBM的I期人体试验。目的是使用宠物狗与 自发GBM，以证明联合免疫疗法的安全性和有效性。我们提出了两 具体目标：1。确定免疫检查点阻断在自发性 与标准护理组合的犬GBM，和2.评估免疫介导基因的疗效 与CD 200阻断剂联合治疗以增强抗胶质瘤免疫治疗。 !