Novel diagnostics for autoimmunity from checkpoint inhibitor immune therapy

检查点抑制剂（CPI）治疗已经改变了实体瘤的治疗。范围内的临床缓解 20- 25%，生存期延长，已报告用于肿瘤，如恶性黑色素瘤和非恶性黑色素瘤。 小细胞肺癌，以前的反应率很低，预后很差。当前治疗块 PD-1/PD-L1和CTLA-4，还有其他正在开发的靶点，如LAG 3。但这些 基于免疫的治疗可能导致不良事件。不受限制的免疫激活导致自身免疫， 特别是内分泌疾病，包括甲状腺炎、垂体炎和肾上腺炎。我们首先报道了 在接受PD-1/PD-L1轴抑制剂治疗的老年个体中发生酮症倾向性糖尿病，以及 随后的其他研究已经确定高血糖症是PD-1/PD-L1的CPI治疗的结果 对手。然而，这些激素缺乏可导致相当大的发病率和长期的 住院因此，在个体出现代谢综合征之前对其进行识别可以使其能够被诊断为代谢综合征。 预防与免疫治疗的副作用相关的发病率，甚至打开免疫治疗的可能性。 选择性免疫调节，以防止这种情况发生在那些处于危险之中。为了解决这个问题，我们开发了 基于垂死细胞释放碎片的原理，测定患者血清中β细胞死亡的测定 以细胞特异性表观遗传模式进入循环系统。我们的初步研究， 接受CPI治疗的癌症患者表明，这种测量方法可以识别出将发展为 糖尿病在临床发病前基于这一成功，我们建议开发甲基化标记物， 用于检测肾上腺和垂体组织损伤的特异性测定，并进一步研究β细胞衍生的 病人的DNA最近的一项综述表明，垂体炎和肾上腺功能不全可能发生在 在接受抗CTLA-4 mAb治疗的患者中，超过16%的患者和接受抗CTLA-4 mAb治疗的患者中， 抗PD-1/PD-L1阻断。此外，内分泌疾病，如垂体或肾上腺功能不全是困难的 诊断没有动态内分泌检测，这只能确定不足后，它已导致器官 杀伤性我们对胰岛素基因的分析以及最近对检测β-胰岛素受体的胰岛素抵抗基因的分析的经验 细胞死亡已经显示了我们使用这种方法的能力，并使用它来发现临床上有意义的结果。 这些检测将满足一个重要的未满足的医疗需求：识别患有内分泌疾病的患者， 免疫治疗的并发症

Checkpoint inhibitor (CPI) therapy has transformed treatment of solid tumors. Clinical responses in the range of 20-25%, with prolonged survival, have been reported for tumors, such as malignant melanoma and non- small cell lung cancer, that previously had poor response rates and dismal prognoses. Current therapies block PD-1/PD-L1 and CTLA-4, and there are other targets being developed such as LAG3. However, these immune-based therapies can lead to adverse events. Unrestricted immune activation leads to autoimmunity, in particular endocrinopathies including thyroiditis, hypophysitis, and adrenalitis. We first reported the development of ketosis prone diabetes in elderly individuals treated with inhibitors of the PD-1/PD-L1 axis, and subsequently other studies have identified hyperglycemia as a consequence of CPI therapy with PD-1/PD-L1 antagonists. These hormone deficiencies, however, can result in considerable morbidity and prolonged hospitalization. Therefore, identifying individuals before they present with metabolic syndromes may enable the prevention of morbidity associated with the adverse effects of immune therapy and even open the possibility of selective immune modulation to prevent this occurrence in those at risk. To address this gap we developed assays to measure β cell death in serum of patients, based on the principle that dying cells release fragments of DNA into the circulation with cell-specific epigenetic patterns. Our preliminary studies from patients with cancers who were treated with CPIs indicated that this measurement may identify individuals who will develop diabetes prior to its clinical onset. Building upon this success, we propose to develop methylation marker specific assays for detecting adrenal and pituitary tissue damage and to further study changes in β cell derived DNA in patients. A recent review has shown that hypophysitis and adrenal insufficiency may be found in greater than 16% of individuals treated with anti-CTLA-4 mAb and in more than 5% of patients treated with anti-PD-1/PD-L1 blockade. In addition, endocrinopathies such as pituitary or adrenal insufficiency are difficult to diagnose without dynamic endocrine testing, which can only identify the insufficiency after it has led to organ destruction. Our experience with the analysis of the insulin gene and recently the IGRP gene for detection of β cell death has shown our ability to work with this approach and to use it to find clinically meaningful outcomes. These assays will fulfill an important unmet medical need: to identify patients who are developing endocrine complications from immunotherapy.