Examining the impact of endogenous CD28 signaling on CAR T cells

项目摘要/总结。 免疫细胞工程的最新进展彻底改变了血液癌症的治疗。遗传 T细胞的修饰，其生理工作是杀死我们全身的感染和突变细胞， 嵌合抗原受体（汽车）可以重定向T细胞杀伤活性，以对抗表达某些抗原的恶性细胞。 靶向蛋白质。汽车被构建为模拟生理T细胞信号传导，这在其 需要由T细胞受体（TCR）和共受体（如CD 28）提供的两种信号来诱导T细胞增殖。 细胞功能多发性骨髓瘤（MM）是一种常见的无法治愈的血癌，最近的临床研究表明， CAR T细胞在治疗对标准治疗没有反应的患者方面非常有效， 化疗尽管如此，大多数MM患者在CAR T细胞治疗的一年内复发， 他们的复发并不明显。本拨款申请中提出的项目的长期目标是 利用我们的知识或T细胞信号传导，使CAR T细胞治疗MM更有效。为此我们 发现CAR T细胞上的内源性CD 28破坏了它们杀死表达CD 28刺激性T细胞的MM细胞的能力。 蛋白质CD 80和CD 86。然而，相同的内源性CD 28对于制造CAR T细胞是必不可少的， 他们还发现，在CAR T细胞制造过程中提供的CD 28信号有助于确定 肿瘤杀手CAR T细胞有多好拟议的研究寻求1）确定操纵CD 28的方法 在CAR T细胞制造过程中的信号传导，可以提高其杀死患者中MM细胞的长期能力，以及 2)确定内源性CD 28信号传导如何导致CAR T细胞功能障碍。这些研究的结果将 具有直接的临床意义，因为对CAR T细胞制造过程的调整可以迅速 一种阻断CD 28激活的药物阿巴西普已经被用于治疗患有 类风湿关节炎

Project Abstract/Summary. Recent advances in immune cell engineering have revolutionized the treatment of blood cancers. Genetic modification of T cells, whose physiological job is to kill infected and mutant cells throughout our bodies, with Chimeric Antigen Receptors (CARs) can redirect T cell killing activity against malignant cells that express certain target proteins on their surface. CARs are built to mimic physiological T cell signaling, which is unique in its requirement for two signals provided by the T cell receptor (TCR) and co-receptors, such as CD28, to induce T cell function. Recent clinical studies in multiple myeloma (MM), a common incurable blood cancer, have shown that CAR T cells are remarkably effective at treating patients who do not respond to standard of care chemotherapies. Despite this, most MM patients relapsed within a year of CAR T cell therapy and the cause of their relapses was not readily apparent. The long-term goal of the project proposed in this grant application is to use our knowledge or T cell signaling to make CAR T cell therapy for MM more effective. To this end, we have found that endogenous CD28 on CAR T cells disrupts their ability to kill MM cells that express CD28 stimulatory proteins CD80 and CD86. However, the same endogenous CD28 is essential for making CAR T cells and we have also found that the CD28 signal provided during the CAR T cell manufacturing process helps determine how good of tumor killers CAR T cells become. Proposed studies seek to 1) identify ways to manipulate CD28 signaling during CAR T cell manufacture that can improve their long-term ability to kill MM cells in patients, and 2) determine how endogenous CD28 signaling causes dysfunction of CAR T cells. Results of these studies will have direct clinical implications because adjustments to the CAR T cell manufacturing process could be rapidly implemented and a drug that blocks CD28 activation, abatacept, is already used to treat people suffering from rheumatoid arthritis.