Correlative biomarkers of IL-6 blockade combined with checkpoint inhibition

IL-6阻断联合检查点抑制的相关生物标志物

• 批准号: 10208830
• 负责人: Jeffrey S Weber
• 金额: $ 59.34万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208830
• 关键词: Acute-Phase Proteins; Aftercare; Antigen-Presenting Cells; Biological Assay; Biological Markers; Biological Response Modifiers; Blocking Antibodies; Blood Cells; Blood specimen; C-reactive protein; Cell physiology; Cells; Charge; Combination immunotherapy; Consult; Data; Dendritic Cells; Dose; Evaluation; Flow Cytometry; Gene Expression Profile; Genetic Transcription; Immune; Immunohistochemistry; Immunosuppression; Immunotherapy; Institutional Review Boards; Interleukin 6 Receptor; Interleukin-6; Liver; MALDI-TOF Mass Spectrometry; Mass Spectrum Analysis; Metastatic Melanoma; Nivolumab; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Proteins; Resistance; Resolution; Role; Sampling; Serum; T-Lymphocyte; Toxic effect; Tumor Markers; anti-PD1 antibodies; base; checkpoint inhibition; chemotherapy; clinical efficacy; cytokine; design; immune checkpoint blockade; immune-related adverse events; improved; insight; ipilimumab; macrophage; melanoma; peripheral blood; phase 2 study; phase II trial; primary endpoint; prognostic; programmed cell death ligand 1; response; single-cell RNA sequencing; therapy resistant; tocilizumab; transcriptome sequencing; trial design; tumor

This proposal is based on an analysis of serum from melanoma patients treated with the PD-1 antibody nivolumab (NIVO) showing that high levels of IL-6 and acute phase reactants (APP) induced by IL-6 like C- reactive protein (CRP) are associated with poor survival. We hypothesize that CRP and other APP induced by IL-6 are associated with resistance to checkpoint inhibition in melanoma, and are immunosuppressive. This is supported by our preliminary data showing that CRP levels are associated with low response rates and short survival with NIVO or ipilimumab (IPI). IL-6 promotes the synthesis of CRP and other APPs from the liver, and its levels are also associated with low response rates, short survival and therapeutic resistance in patients receiving NIVO, IPI or combination immune checkpoint blockade (ICB). Patients with low IL-6 at baseline or after treatment with ICB have high response rates and long survivals. To overcome the immune suppression observed with CRP and reverse ICB resistance associated with high IL-6, we will add the IL-6 receptor blocking antibody tocilizumab to IPI and NIVO in patients with metastatic melanoma. Our overarching hypothesis is that levels of IL-6 and CRP in baseline serum and other biomarkers in serum, PBMCs and tumor will predict efficacy and toxicity in a phase II trial of IPI/NIVO with tocilizumab and that IL-6 blockade will augment the efficacy of, and reduce toxicity from combined ICB. These biomarkers will provide insight into host/tumor mediators of ICB and help direct patients to the most effective immunotherapy based on their baseline and on-treatment levels of IL-6/CRP and other biomarkers. Co-primary endpoints of the trial include best overall response rate and toxicity since IL-6 blockade has also been shown to reduce immune-related adverse events with immunotherapy. A Simon two-stage design trial will include 67 patients that will receive the triple combination and will be supported by BMS. In this proposal, we wish to support the correlative marker studies based on that phase II trial. Analyses of the serum, tumor and peripheral blood will be carried out to establish biomarkers of efficacy and toxicity and help understand the basis for resistance to combination ICB in melanoma based on three specific aims: 1. To determine if baseline levels, or on-treatment changes in a serum mass spectrometry-MALDI-TOF protein signature and acute phase reactants and cytokines are associated with response and toxicity in a phase II trial of IPI/NIVO with the IL-6 receptor blocking antibody tocilizumab; 2. To determine if baseline or on-treatment changes in peripheral blood and tumor T cell phenotype and function assessed by multi-parameter flow cytometry, Ab-Seq and IsoLight assays, peripheral blood dendritic cell phenotype and function and tumor class I and II expression, PD-L1 levels and RNA seq signatures are associated with response and toxicity in a phase II study of IPI/NIVO with tocilizumab; and 3. To integrate the serum, peripheral blood and tumor biomarkers of aims 1 and 2 to assess if a consolidated signature is associated with response and toxicity in a phase II study of IPI/NIVO with tocilizumab.

该提案基于对接受 PD-1 抗体治疗的黑色素瘤患者血清的分析 nivolumab (NIVO) 显示高水平的 IL-6 和急性期反应物 (APP) 由 IL-6 诱导，如 C- 反应蛋白（CRP）与较差的生存率相关。我们假设 CRP 和其他 APP 诱导 IL-6 的作用与黑色素瘤中检查点抑制的抵抗有关，并且具有免疫抑制作用。 我们的初步数据证明了这一点，表明 CRP 水平与低反应率相关 NIVO 或 ipilimumab (IPI) 的生存期较短。 IL-6促进CRP和其他APP的合成 肝脏，其水平也与低反应率、短生存期和治疗耐药性相关 接受 NIVO、IPI 或联合免疫检查点阻断 (ICB) 的患者。 IL-6 水平较低的患者 基线或 ICB 治疗后有较高的缓解率和较长的生存期。为了克服免疫 观察到的 CRP 抑制和与高 IL-6 相关的逆转 ICB 耐药性，我们将添加 IL-6 转移性黑色素瘤患者中针对 IPI 和 NIVO 的受体阻断抗体托珠单抗。我们的首要任务 假设基线血清中的 IL-6 和 CRP 水平以及血清、PBMC 和肿瘤中的其他生物标志物水平 将在使用托珠单抗的 IPI/NIVO II 期试验中预测疗效和毒性，并且 IL-6 阻断将 增强联合 ICB 的功效并降低其毒性。这些生物标志物将提供深入了解 ICB 的宿主/肿瘤介质，并根据患者的情况帮助指导患者接受最有效的免疫治疗 IL-6/CRP 和其他生物标志物的基线和治疗中水平。试验的共同主要终点包括 自IL-6阻断以来最佳的总体缓解率和毒性也被证明可以减少免疫相关的 免疫治疗的不良事件。 Simon 的两阶段设计试验将包括 67 名患者，他们将接受 三重组合将得到BMS的支持。在本提案中，我们希望支持相关的 基于该 II 期试验的标志物研究。将进行血清、肿瘤和外周血的分析 建立功效和毒性的生物标志物，并帮助了解组合耐药性的基础 黑色素瘤中的 ICB 基于三个具体目标： 1. 确定基线水平或治疗中是否发生变化 在血清质谱-MALDI-TOF 蛋白质特征和急性期反应物和细胞因子中 与使用 IL-6 受体阻断抗体的 IPI/NIVO II 期试验中的反应和毒性相关 托珠单抗； 2. 确定外周血和肿瘤 T 细胞的基线或治疗中是否发生变化 通过多参数流式细胞术、Ab-Seq 和 IsoLight 检测、外周血检测评估表型和功能 血液树突状细胞表型和功能以及肿瘤 I 类和 II 类表达、PD-L1 水平和 RNA seq 在 IPI/NIVO 与托珠单抗的 II 期研究中，特征与反应和毒性相关；和 3. 整合目标 1 和 2 的血清、外周血和肿瘤生物标志物，以评估是否可以整合 在 IPI/NIVO 与托珠单抗的 II 期研究中，特征与反应和毒性相关。