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Translating cellular immunotherapies for autoimmunity to canine clinical trials

将自身免疫细胞免疫疗法转化为犬类临床试验

基本信息

批准号：
9982789
负责人：
NICOLA J MASON
金额：
$ 85.92万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982789
关键词：
Adhesions Adrenal Cortex Hormones Affect Animals Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Bulla Cancer Patient Canis familiaris Cell Therapy Cells Cellular immunotherapy Cessation of life Chronic Clinical Research Clinical Treatment Clinical Trials Complex Data Dependence Disease Disease remission Dog Diseases Down-Regulation Engineered Gene Enrollment FDA approved Face Fostering Future Histologic Human Immune system Immunity Immunosuppression Immunotherapy Impairment Infection Investigational Therapies MS4A1 gene Malignant Neoplasms Mediating Memory Memory B-Lymphocyte Minor Morbidity - disease rate Motivation Mus Mutation Names Nature Normal tissue morphology Paper Patients Pemphigus Pemphigus Vulgaris Persons Plasmablast Population Positioning Attribute Pre-Clinical Model Rare Diseases Receptors, Antigen, B-Cell Recurrence Research Research Project Grants Risk Safety Second Primary Cancers Serological Serum Skin System T-Cell Receptor T-Lymphocyte Technology Testing Time Toxic effect Translating Translations Validation Veterinary Medicine Work anti-CD20 autoreactive B cell cancer therapy collaborative environment cytokine release syndrome cytotoxicity desmoglein experience experimental study first-in-human high reward high risk human disease innovation interest isoimmunity mortality risk mouse model novel pre-clinical pre-clinical therapy preclinical efficacy preclinical safety preservation rituximab side effect standard of care

项目摘要

Project summary: Autoimmunity occurs when the body's immune system mistakenly attacks normal tissues, leading to disease. Treatments for autoimmunity chronically suppress the immune system, which risks fatal infection; thus the ideal therapy would eliminate only the disease-causing autoimmune cells while preserving normal immunity. We recently developed a novel gene-engineered chimeric autoantibody receptor T cell (CAAR-T) therapy that uses the autoantigen targeted in disease to direct T cell cytotoxicity against only those B cells that express autoantigen-specific B cell receptors (BCRs). We have shown that CAAR-Ts cause complete histologic and serologic remission of autoantibody (autoAb)-mediated disease in an experimental mouse model and engraft to form memory CAAR-Ts that can provide lasting protection against disease recurrence. In considering how to translate CAAR-T technology to first-in-human trials, a challenge arises given that most autoimmune patients do not face imminent death from their disease, unlike the first cancer patients treated with gene-engineered cellular therapies. The current preclinical pipeline relies on mice whose disease is artificially induced and treated shortly after disease induction. Cytokine release syndrome does not occur in mice despite being one of the most common toxicities in cancer patients. The field has not pursued better preclinical models given the risks of time and money involved in experimenting in a new animal species. Given the curative potential for CAAR-T in autoimmunity and the increasing interest in developing cellular therapies for non-oncologic indications, we believe it is now crucial to establish a higher preclinical standard. We thus seek to establish dogs with naturally occurring autoimmune disease as an ideal preclinical system for assessing cellular immunotherapies, which we believe will better predict the safety and efficacy of human therapies than experimental mouse models. This proposal meets the high-risk, high-reward nature of the transformative R01 program, as gene-engineered cellular therapies have never been tested in any naturally occurring autoimmune disease. The successful treatment of autoimmunity in dogs with CAAR-T would not only be a breakthrough in veterinary medicine, but would also establish dogs as an ideal species for preclinical validation of human cellular immunotherapies and provide compelling evidence for doctors and patients to enroll for future CAAR-T first-in-human trials. Ultimately, our work could facilitate the translation of cellular immunotherapies for a broad range of canine and human diseases.

项目概要：当人体的免疫系统错误地攻击正常组织时，就会发生自身免疫，从而导致疾病。自身免疫的治疗长期抑制免疫系统，这有致命感染的风险;因此，理想的治疗方法是只清除致病的自体免疫细胞，同时保持正常的免疫力。我们最近开发了一种新的基因工程嵌合自身抗体受体T细胞（CAAR-T）疗法，使用疾病中靶向的自身抗原来指导T细胞的细胞毒性，仅针对那些表达以下抗原的B细胞：自身抗原特异性B细胞受体（BCR）。我们已经证明CAAR-Ts引起完全的组织学和病理学改变，在实验小鼠模型和移植物中自身抗体（autoAb）介导的疾病的血清学缓解形成记忆CAAR-T，可以提供持久的保护，防止疾病复发。考虑如何将CAAR-T技术转化为首次人体试验，鉴于大多数自身免疫性患者不像第一批接受基因工程治疗的癌症患者，细胞疗法目前的临床前管道依赖于小鼠，其疾病是人工诱导的，在疾病诱导后不久进行治疗。细胞因子释放综合征在小鼠中不发生，尽管它是癌症患者最常见的毒性反应。该领域没有追求更好的临床前模型，在一个新的动物物种上进行实验所涉及的时间和金钱的风险。考虑到治疗的潜力， CAAR-T在自身免疫中的作用以及对开发非肿瘤细胞疗法的兴趣日益增加适应症，我们认为现在至关重要的是建立一个更高的临床前标准。因此，我们寻求建立患有自然发生的自身免疫性疾病的犬作为评估细胞免疫功能的理想临床前系统免疫疗法，我们相信这将更好地预测人类治疗的安全性和有效性，实验小鼠模型。该提案符合变革性R 01的高风险、高回报性质计划，因为基因工程细胞疗法从未在任何自然发生的自身免疫性疾病中进行过测试。疾病用CAAR-T成功治疗狗的自身免疫性不仅是一个突破，兽医学，但也将建立狗作为一个理想的物种，为临床前验证的人细胞免疫疗法，并为医生和患者注册未来的CAAR-T提供令人信服的证据首次人体试验最终，我们的工作可以促进细胞免疫疗法的广泛应用。一系列犬类和人类疾病。