MICA: "Off-the-Shelf" CAR-based immunotherapy of SLE by targeting B cells and plasma cells

MICA：“现成的”基于 CAR 的 SLE 免疫疗法，靶向 B 细胞和浆细胞

• 批准号: MR/X004600/1
• 负责人: Lyra Onintsoa Randzavola
• 金额: $ 64.64万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX004600%2F1
• 关键词: MICA; Off; Shelf; CAR; based

Lupus is a life-long illness where the immune system produces autoantibodies to attack its own healthy tissue causing inflammation and damage to organs such as the kidney and heart. Worldwide 1 in 2000 women are affected by lupus. Yet no cure has been identified and current treatments are not well tolerated and are only partially effective. One way to effectively treat lupus patients would be to eliminate their autoreactive B cells which are known to be the source of autoantibodies. Studies in mice and humans have shown that chimaeric antigen receptor (CAR)-T cells targeting B cells successfully eliminate most of the disease manifestations achieving clinical remission. This fellowship aims to develop a new CAR-based treatment by using specialised T cells called iNKT cells. These cells are unique because they recognise lipids on the surface of B cells. Since lipids are common to all individuals, CAR-iNKT cells can be made from one healthy person and used to treat any lupus patient without the risk of harm to the patient. The main purposes of this project are i) to compare the efficacy of CAR approaches targeting B cells (using CD19 as marker) versus those targeting plasma cells (identified by BCMA); ii) to develop CAR-iNKT cells and test their of ability to treat lupus in an in vivo experimental model; iii) to explore in vitro how lupus patient B cells respond to CAR-modified cells. The proposed research will provide the pre-clinical rationale for clinical development of the most effective CAR-based immunotherapy as a potentially transformative treatment for patients with SLE.

狼疮是一种终身疾病，免疫系统产生自身抗体攻击自身健康组织，导致肾脏和心脏等器官炎症和损伤。在全球范围内，每2000名女性中就有1名受到狼疮的影响。然而，还没有确定治愈方法，目前的治疗方法耐受性不好，只有部分有效。一种有效治疗狼疮患者的方法是消除他们的自身反应性B细胞，这是已知的自身抗体的来源。在小鼠和人类中的研究已经表明，靶向B细胞的嵌合抗原受体（CAR）-T细胞成功地消除了大多数疾病表现，实现了临床缓解。该研究旨在通过使用称为iNKT细胞的专门T细胞开发一种新的基于CAR的治疗方法。这些细胞是独特的，因为它们识别B细胞表面的脂质。由于脂质对所有个体都是常见的，因此CAR-iNKT细胞可以从一个健康人中制备，并用于治疗任何狼疮患者，而不会对患者造成伤害。该项目的主要目的是i）比较靶向B细胞（使用CD 19作为标记物）的CAR方法与靶向浆细胞（通过BCMA鉴定）的CAR方法的功效; ii）开发CAR-iNKT细胞并在体内实验模型中测试其治疗狼疮的能力; iii）体外探索狼疮患者B细胞如何对CAR修饰的细胞作出反应。拟议的研究将为临床开发最有效的基于CAR的免疫疗法提供临床前依据，作为SLE患者的潜在变革性治疗。