Canine Immuno Neurotherapeutics

犬免疫神经治疗

基本信息

批准号：
10247895
负责人：
M R Chambers
金额：
$ 52.02万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247895
关键词：
Accounting Address Adult Aftercare Animal Model Animals Antigens Antitumor Response Archives Beds Benign Biological Biological Assay Biology Blood specimen Brain Brain Neoplasms Canis familiaris Caring Cells Central Nervous System Neoplasms Clinical Clinical Research Collaborations Collection Combination immunotherapy Consent Coupled Databases Diagnostic Diet Dose Environment Epitope spreading Evaluation Freezing Future Genomics Glioblastoma Glioma Helper-Inducer T-Lymphocyte Histologic Histopathology Hospitalization Human Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunotherapeutic agent Immunotherapy In complete remission Infection Inflammatory Inflammatory Response Injections Interleukin-12 Kynurenine Laboratories Lymphocyte Magnetic Resonance Imaging Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Measurement Measures Medicine Modeling Monitor Mononuclear Mononuclear Leukocytes Mus Nervous System Physiology Normal Cell Oncology Oncolytic viruses Outcome Outpatients Patients Plasma Primary Brain Neoplasms Process Progression-Free Survivals Progressive Disease Regulatory T-Lymphocyte Research Resected Safety Saliva Sampling Schedule Serum Simplexvirus Stable Disease Standardization T cell anergy Testing Therapeutic Studies Time Tissue Banks Toxic effect Translating Tryptophan Tumor Antigens Tumor Tissue Tumor Volume Veterinary Medicine Viral Viral Antigens Virus anti-tumor immune response antigen-specific T cells base care costs clinical application clinical implementation cohort combinatorial companion animal comparative cytokine design dog genome effective therapy exome sequencing experience follow-up immune checkpoint improved information model inhibitor/antagonist innate immune checkpoint innovation model design mortality neoplastic cell nonhuman primate novel novel strategies oncolytic herpes simplex virus oncolytic virotherapy partial response peripheral blood pet animal phase 1 study phase I trial predicting response recruit response secondary endpoint small molecule small molecule inhibitor standard of care success transcriptome sequencing transcriptomics translational study tumor

Accounting Address Adult Aftercare Animal Model Animals Antigens Antitumor Response Archives Beds Benign Biological Biological Assay Biology Blood specimen Brain Brain Neoplasms Canis familiaris Caring Cells Central Nervous System Neoplasms Clinical Clinical Research Collaborations Collection Combination immunotherapy Consent Coupled Databases Diagnostic Diet Dose Environment Epitope spreading Evaluation Freezing Future Genomics Glioblastoma Glioma Helper-Inducer T-Lymphocyte Histologic Histopathology Hospitalization Human Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunotherapeutic agent Immunotherapy In complete remission Infection Inflammatory Inflammatory Response Injections Interleukin-12 Kynurenine Laboratories Lymphocyte Magnetic Resonance Imaging Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Measurement Measures Medicine Modeling Monitor Mononuclear Mononuclear Leukocytes Mus Nervous System Physiology Normal Cell Oncology Oncolytic viruses Outcome Outpatients Patients Plasma Primary Brain Neoplasms Process Progression-Free Survivals Progressive Disease Regulatory T-Lymphocyte Research Resected Safety Saliva Sampling Schedule Serum Simplexvirus Stable Disease Standardization T cell anergy Testing Therapeutic Studies Time Tissue Banks Toxic effect Translating Tryptophan Tumor Antigens Tumor Tissue Tumor Volume Veterinary Medicine Viral Viral Antigens Virus anti-tumor immune response antigen-specific T cells base care costs clinical application clinical implementation cohort combinatorial companion animal comparative cytokine design dog genome effective therapy exome sequencing experience follow-up immune checkpoint improved information model inhibitor/antagonist innate immune checkpoint innovation model design mortality neoplastic cell nonhuman primate novel novel strategies oncolytic herpes simplex virus oncolytic virotherapy partial response peripheral blood pet animal phase 1 study phase I trial predicting response recruit response secondary endpoint small molecule small molecule inhibitor standard of care success transcriptome sequencing transcriptomics translational study tumor

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项目摘要

ABSTRACT: The dog is an ideal large animal model for diagnostic and therapeutic studies and can be used to translate successes to human patients while providing compassionate care to animals and advancing the field of veterinary medicine. Pet dogs share their environment, and oftentimes their diet, with their owners. Dogs and humans develop sporadic benign and malignant brain tumors at about the same rate and with similar histopathology. Dogs are often euthanized due to the cost of care. Thus, the spontaneously occurring canine brain tumor represents an ideal opportunity to improve the lives of people as well as pets through comparative oncology and genomics and the “One Medicine” approach to research and direct clinical application. We propose a multi-institutional consortium to test an innovative combinatorial immunotherapeutic approach in dogs that spontaneously and sporadically develop malignant glial brain tumors that resemble in most important aspects, high-grade malignant gliomas in humans. Our approach will inject a clinical grade oncolytic herpes simplex virus (HSV) M032 that expresses human interleukin-12 (IL-12) into the resected tumor bed. Dog lymphocytes fully respond to human IL-12 [1] and oncolytic HSV infect and kill canine (as well as mouse, non-human primate, human) tumor cells, creating a potent local inflammatory response and an antigen-rich tumor cell debris field. Therefore, we would anticipate that this virally-based immunotherapeutic approach would likely be as effective in dogs with brain tumors as in humans with brain tumors. We will conduct longitudinal safety, survival and correlative biology evaluations as a means of assessing the dog as an appropriate and informative model for design and implementation of clinical studies in humans with high-grade malignant brain tumors. To extend these findings, we propose, in subsequent studies, to combine the HSV immunotherapy approach with molecules that block the action of innate checkpoint inhibitor(s). These studies are designed to address key issues of safety and efficacy of combinatorial immunotherapy in the dog that can be translated to humans with malignant gliomas. Malignant gliomas are the most common primary brain tumors in humans, accounting for 30% of all primary central nervous system (CNS) tumors in adults. [2] With few major advances in decades, there has been no significant reduction in mortality and only a modest improvement in median survival. Recently, objective responses and long-term survivals have been observed in human glioma patients who have received oncolytic virotherapy and a Phase I trial is currently underway at UAB in patients using M032 alone. New approaches to utilize checkpoint inhibitors promises improved efficacy, but the ability to develop more effective combinatorial approaches has been slow, in large part due to lack of a faithful model of spontaneous glioblastoma multiforme (GBM) in immunocompetent hosts. Thus, the spontaneously occurring canine brain tumor represents an ideal opportunity to improve the lives of people and pets through comparative oncology and genomics using the “One Medicine“ approach to research and direct clinical application.

抽象的：该狗是用于诊断和治疗研究的理想大型动物模型，可用于翻译为人类患者取得成功，同时为动物提供富有同情心的护理并推动兽医医学。宠物犬与主人共享他们的环境，通常是他们的饮食。狗和人类以大约相同的速率发展零星良性和恶性脑肿瘤组织病理学。由于护理费用，狗通常被安乐死。那是赞助的犬脑肿瘤是通过比较改善人们和宠物生活的理想机会肿瘤学和基因组学以及研究和直接临床应用的“一种医学”方法。我们建议一个多机构的财团，用于测试狗的创新组合免疫治疗方法自发和偶尔会发展出类似于最重要方面的恶性神经胶质脑肿瘤，人类中的高级恶性神经胶质瘤。我们的方法将注入临床等级的溶瘤疱疹病毒（HSV）M032将人白细胞介素12（IL-12）表达为切除的肿瘤床。狗淋巴细胞完全应对人IL-12 [1]和溶瘤HSV感染并杀死犬（以及小鼠，非人类灵长类动物，人）肿瘤细胞，产生潜在的局部炎症反应和富含抗原的肿瘤细胞碎片场。因此，我们预计这种虚拟的免疫治疗方法可能会同样有效在患有脑肿瘤的狗中，就像在患有脑肿瘤的人类中一样。我们将进行纵向安全，生存和相关生物学评估是评估狗作为适当且信息丰富的模型的一种手段具有高度恶性脑肿瘤的人类临床研究的设计和实施。扩展这些在随后的研究中，我们提出发现，将HSV免疫疗法方法与分子结合在一起，阻止先天检查点抑制剂的作用。这些研究旨在解决安全的关键问题组合免疫疗法在狗中的有效性，可以转化为具有恶性神经胶质瘤的人。恶性神经胶质瘤是人类中最常见的原发性脑肿瘤，占所有原发性的30％成人中枢神经系统（CNS）肿瘤。 [2]几十年来几乎没有重大进展，没有死亡率的显着降低，中位存活率仅适度改善。最近，客观在接受肿瘤的人神经胶质瘤患者中，已经观察到反应和长期生存目前，仅使用M032的患者，目前，在UAB正在进行病毒疗法和I期试验。新方法利用检查点抑制剂有望提高效率，但具有更有效组合的能力方法一直很慢，在很大程度上是由于缺乏赞助胶质母细胞瘤的忠实模型（GBM）在免疫能力的宿主中。这是赞助的犬脑肿瘤代表理想的通过比较肿瘤学和基因组学改善人们和宠物生活的机会医学“研究和直接临床应用方法。