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

狼疮是一种终生疾病，免疫系统会产生自身抗体来攻击自己的健康组织，导致炎症和对肾脏和心脏等器官的损害。在世界范围内，每2000名妇女中就有1人患有狼疮。然而，目前还没有找到治愈方法，目前的治疗方法耐受性不好，只有部分有效。有效治疗狼疮患者的一种方法是消除他们的自身反应性B细胞，这种细胞被认为是自身抗体的来源。在小鼠和人类身上的研究表明，以B细胞为靶点的嵌合体抗原受体(CAR)-T细胞成功地消除了大多数疾病的表现，实现了临床缓解。该奖学金旨在通过使用被称为iNKT细胞的特殊T细胞来开发一种基于CAR的新疗法。这些细胞是独一无二的，因为它们识别B细胞表面的脂类。由于脂质对所有人都是常见的，CAR-iNKT细胞可以从一个健康的人身上制造出来，用于治疗任何狼疮患者，而不会对患者造成伤害。本项目的主要目的是：i)比较以CD19为标记物的CAR方法与以浆细胞为靶点的CAR方法的有效性；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)探讨体外CAR修饰的细胞对狼疮患者B细胞的反应。这项拟议的研究将为临床开发最有效的基于CAR的免疫疗法作为SLE患者潜在的变革性治疗提供临床前理论基础。

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.