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

• 批准号: 10454148
• 负责人: NICOLA J MASON
• 金额: $ 82.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454148
• 关键词: Adhesions; Adrenal Cortex Hormones; Affect; Animals; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Antigen Receptor; 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; Recurrence; Research; Research Project Grants; Risk; Safety; Second Primary Cancers; Serology; 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

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.

项目摘要： 当人体的免疫系统错误攻击正常组织，导致疾病时，会发生自身免疫性。 自身免疫的治疗长期抑制免疫系统，这种免疫系统有可能致命感染；因此 理想的疗法只能消除引起疾病的自身免疫细胞，同时保持正常免疫力。 我们最近开发了一种新型的基因工程嵌合自身抗体受体T细胞（CAAR-T）疗法 使用针对疾病的自身抗原来指导T细胞细胞毒性，仅针对那些表达的B细胞 自身抗原特异性B细胞受体（BCR）。我们已经表明，CAAR-TS引起完整的组织学和 在实验小鼠模型中自身抗体的血清学缓解（AUTOAB）介导的疾病 形成记忆CAAR-TS，可以提供持久的保护，以防止疾病复发。在考虑如何 将CAAR-T技术转换为首次人类试验，鉴于大多数自身免疫性患者 与第一批用基因工程治疗的癌症患者不同，不要面对即将死亡的死亡 细胞疗法。当前的临床前管道依赖于人为诱导的疾病的小鼠 疾病诱导后不久治疗。尽管是其中之一 癌症患者最常见的毒性。鉴于 在新动物物种中进行实验的时间和金钱风险。鉴于治愈潜力 自身免疫性的CAAR-T和对开发非综合学的细胞疗法的兴趣日益增加 迹象，我们认为建立更高的临床前标准至关重要。因此，我们试图建立 天然发生自身免疫性疾病的狗是评估细胞的理想临床前系统 免疫疗法，我们认为这将更好地预测人类疗法的安全性和功效 实验鼠标模型。该提议符合变革性R01的高风险，高回报的性质 程序，由于基因工程的细胞疗法从未在任何天然发生的自身免疫中进行测试 疾病。成功治疗CAAR-T的狗的自身免疫性不仅是一个突破 兽医医学，但也会将狗作为人类临床前验证的理想物种 细胞免疫疗法，并为医生和患者提供了令人信服的证据 首次人类试验。最终，我们的工作可以促进细胞免疫疗法的翻译 犬类和人类疾病的范围。