(PQ8) Biomarker identification by mass cytometry in peripheral blood of patients with renal cell carcinoma undergoing immune checkpoint therapy

(PQ8) 接受免疫检查点治疗的肾细胞癌患者外周血中通过质谱流式细胞仪进行生物标志物鉴定

• 批准号: 10017923
• 负责人: Wendy Jane Fantl
• 金额: $ 17.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017923
• 关键词: Acute Lymphocytic Leukemia; Address; Adverse event; Affect; Antibodies; Antitumor Response; Autoimmune Process; Awareness; Biological Markers; Blood; Blood Cells; Blood specimen; Buffers; CTLA4 gene; Cell surface; Cells; Clinical; Combined Modality Therapy; Common Terminology Criteria for Adverse Events; Cytometry; Data; Data Set; Development; Goals; Immune; Immune checkpoint inhibitor; Immunologic Markers; Immunotherapeutic agent; Immunotherapy; Incubated; Individual; Inflammatory; Leukemia Acute Lymphoblastic Chemotherapy; Malignant Neoplasms; Measures; Metastatic Melanoma; Modeling; Monitor; Nivolumab; Operative Surgical Procedures; Organ; PD-1 inhibitors; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Pregnancy; Progression-Free Survivals; Recovery; Relapse; Renal Cell Carcinoma; Renal carcinoma; Research; Risk; Sampling; Signal Pathway; Signal Transduction; Standardization; Statistical Methods; Systemic Therapy; Testing; Toxic effect; Translations; Treatment Efficacy; Tube; Up-Regulation; Vertebral column; Whole Blood; Woman; anti-PD-1; base; bevacizumab; biomarker identification; cancer diagnosis; checkpoint inhibition; checkpoint therapy; chemotherapy; clinically significant; computerized tools; cytokine; early phase clinical trial; experience; high dimensionality; hip replacement arthroplasty; hip surgery; immune-related adverse events; improved; innovation; leukemia; men; monocyte; novel; peripheral blood; phase III trial; predicting response; predictive marker; prospective; regression algorithm; response; single cell analysis; targeted agent; targeted treatment; tool; trait

PROJECT SUMMARY Kidney cancer (renal cell carcinoma, RCC) is now the 6th and 10th most common cancer diagnosed in men and women, respectively. Median overall survival for patients with metastatic RCC (mRCC) has improved in the targeted therapy era, but remains modest at 14 months. Immune checkpoint inhibitors (ICI) showed exceptional promise in early clinical trials for mRCC – eventually leading to FDA approval of nivolumab (anti-PD-1) as a second-line treatment in 2016. In 2018, combination therapy with nivolumab plus ipilimumab (anti-cytotoxic T- lymphocyte-associated antigen 4; CTLA-4) demonstrated significant response rates in intermediate- and poor- risk RCC patients and has recently been approved as a first-line mRCC treatment. However, it is still unclear why immune checkpoint inhibitor (ICI) therapies are effective – and remarkably so – in only ~25% of patients with mRCC. There is also increasing awareness of the potential toxicities, and specifically the immune-related adverse events (irAEs), associated with checkpoint inhibitors. Therefore, there is an urgent need to identify mechanistic biomarkers that 1) reliably predict the development of irAEs, and 2) predict the response of mRCC to checkpoint inhibitors. In response to PQ8, our goal is to evaluate whether changes in intracellular signaling responses in peripheral blood immune cells taken before treatment from patients with mRCC could serve as “predictive biomarkers for the onset of immune-related adverse events (irAEs) associated with checkpoint inhibition”. Our group, along with others, has shown that intracellular signaling responses in peripheral blood immune cells are correlated with response to chemotherapy in acute lymphoblastic leukemia (ALL), recovery from hip surgery, and full-term pregnancy. Furthermore, it was recently shown that a patient’s baseline immune state before i) surgery for hip replacement ii) chemotherapy for ALL iii) ICI treatment for metastatic melanoma were determinants of recovery, relapse and progression-free survival respectively. Our proposal is therefore built on the hypothesis that patients with mRCC receiving ICIs differ in their pre-drug immune state which will affect the onset of irAEs and clinical response. To address this, we will perform CyTOF analysis using peripheral blood measuring both cell abundance and intracellular signaling from 60 patients with mRCC before ICI administration. In Aim 1, based on our experience in streamlining the translation of CyTOF to clinical samples, we will use novel agents to standardize whole blood processing enabling the use of CyTOF “at the bedside” to study the immune state pre-treatment with ICIs. In Aim 2, we will adapt multivariate regression algorithms to identify immune correlates for predicting irAEs and clinical response. Novel applications of these powerful statistical methods to mass cytometry datasets will ultimately form the analytical groundwork to examine the relationship between patient-specific immune traits before administration of, irAEs, and treatment efficacy.

项目总结 肾癌(肾细胞癌，RCC)是目前在男性中诊断的第6和第10种常见癌症。 分别是女性。转移性肾细胞癌(MRCC)患者的中位总生存率在 靶向治疗时代，但14个月仍保持温和。免疫检查点抑制物(ICI)显示出异常 MRCC早期临床试验的希望-最终导致FDA批准nivolumab(抗PD-1)作为 2016年二线救治。2018年，用nivolumab联合ipilimumab(抗细胞毒T- 淋巴细胞相关抗原4；CTLA-4)在中等和较差的患者表现出显著的应答率 风险肾细胞癌患者，最近已被批准为一线治疗肾细胞癌。然而，目前仍不清楚 为什么免疫检查点抑制(ICI)疗法只在大约25%的患者中有效--而且非常有效 与mRCC合作。人们也越来越多地意识到潜在的毒性，特别是与免疫相关的 与检查点抑制剂相关的不良事件(IrAE)。因此，迫切需要确定 1)可靠地预测irAEs的发展，2)预测mRCC的反应的机械性生物标志物 到检查站抑制剂。作为对PQ8的反应，我们的目标是评估细胞内信号的变化 肾细胞癌患者治疗前外周血免疫细胞的反应可作为 “与检查点相关的免疫相关不良事件(IrAE)发生的预测性生物标志物 抑制。“。 我们的团队和其他人一起，已经表明外周血液免疫细胞中的细胞内信号反应 与急性淋巴细胞性白血病(ALL)的化疗反应、髋关节手术后的恢复、 还有足月怀孕。此外，最近有研究表明，患者在发病前的基线免疫状态 髋关节置换手术II)ALL的化疗III)转移性黑色素瘤的ICI治疗 分别是恢复、复发和无进展生存的决定因素。因此，我们的建议是建立在 假设接受ICIS治疗的肾细胞癌患者在服药前免疫状态不同，这将 影响irAEs的发生和临床反应。为了解决这个问题，我们将使用以下命令执行CyTOF分析 60例肾细胞癌患者外周血细胞丰度和细胞内信号转导的检测 ICI管理部门。在目标1中，根据我们在简化CyTOF到临床的转换方面的经验 对于样本，我们将使用新的试剂来标准化全血处理，从而实现细胞外基质的使用。 研究ICIS治疗前的免疫状态。在目标2中，我们将采用多元回归 识别免疫相关性的算法，用于预测irAEs和临床反应。它们的新应用 强大的统计方法将最终形成对质量细胞仪数据集的分析基础 给药前患者特异性免疫特征、irAEs和治疗效果之间的关系。