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。T细胞的遗传修饰，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细胞对恶性细胞的杀伤活性，这些恶性细胞在其表面上表达某些靶蛋白。汽车被构建为模拟生理T细胞信号传导，其独特之处在于其需要由T细胞受体（TCR）和共受体（诸如CD 28）提供的两种信号来诱导T细胞功能。多发性骨髓瘤（MM）是一种常见的不可治愈的血癌，最近的临床研究表明，CAR T细胞在治疗对标准化疗无反应的患者方面非常有效。尽管如此，大多数MM患者在CAR T细胞治疗一年内复发，其复发的原因并不明显。该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刺激蛋白CD 80和CD 86的MM细胞的能力。然而，相同的内源性CD 28对于制造CAR T细胞是必不可少的，我们还发现，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伤细胞CAR T细胞的效果。拟议的研究旨在1）确定在CAR T细胞制造过程中操纵CD 28信号传导的方法，这些方法可以提高其杀死患者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实施，并且阻断CD 28活化的药物阿巴西普已经用于治疗患有类风湿性关节炎的人。

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.