Examining the impact of endogenous CD28 signaling on CAR T cells

项目摘要/摘要。 免疫细胞工程的最新进展使血癌的治疗发生了革命性的变化。遗传 修饰T细胞，它的生理工作是杀死我们全身的感染和突变细胞，用 嵌合抗原受体(CARS)可重定向T细胞对表达特定抗原的肿瘤细胞的杀伤活性 它们表面的靶向蛋白质。汽车是为了模仿生理T细胞信号而制造的，这是它的独特之处 需要由T细胞受体(TCR)和辅助受体(如CD28)提供的两个信号来诱导T细胞 细胞功能。最近对多发性骨髓瘤(MM)的临床研究表明，多发性骨髓瘤(MM)是一种常见的不可治愈的血癌 CAR T细胞在治疗对标准护理无效的患者方面非常有效 化疗。尽管如此，大多数多发性骨髓瘤患者在接受CAR T细胞治疗一年内复发，其原因是 他们的旧病复发并不是很明显。在这项赠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，使CAR T细胞治疗多发性骨髓瘤更有效。为此，我们有 发现CAR T细胞上的内源性CD28破坏了它们杀伤表达CD28刺激性的MM细胞的能力 蛋白质CD80和CD86。然而，同样的内源性CD28对于制造CAR T细胞和我们 我还发现，在汽车T细胞制造过程中提供的CD28信号有助于确定 肿瘤杀手CAR T细胞变得有多好。拟议的研究试图1)找出操纵CD28的方法 CAR T细胞制造过程中的信号转导可以提高其长期杀伤患者多发性骨髓细胞的能力，以及 2)确定内源性CD28信号如何导致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能会迅速 一种阻止CD28激活的药物abatacept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.