Correlative biomarkers of IL-6 blockade combined with checkpoint inhibition

该提议是基于对来自用PD-1抗体治疗的黑色素瘤患者的血清的分析 纳武单抗（NIVO）显示高水平的IL-6和由IL-6诱导的急性期反应物（APP）如C- 反应蛋白（CRP）与生存率低有关。我们假设CRP和其他APP诱导 与黑色素瘤中对检查点抑制的抗性相关，并且是免疫抑制性的。 我们的初步数据显示CRP水平与低应答率相关， NIVO或伊匹单抗（IPI）的生存期短。IL-6促进CRP和其他APP的合成， 肝脏，其水平也与反应率低，生存期短和治疗抗性有关 在接受NIVO、IPI或联合免疫检查点阻断（ICB）的患者中。低IL-6患者， 基线或ICB治疗后有高应答率和长生存期。为了克服免疫力 观察到CRP的抑制和与高IL-6相关的逆转ICB抵抗，我们将加入IL-6 转移性黑色素瘤患者IPI和NIVO的受体阻断抗体托珠单抗。我们的总体 假设基线血清中IL-6和CRP水平以及血清、PBMC和肿瘤中的其它生物标志物 将预测IPI/NIVO与托珠单抗的II期试验的疗效和毒性，IL-6阻断将 增强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，并帮助指导患者根据其 IL-6/CRP和其他生物标志物的基线和治疗水平。试验的协同主要终点包括 由于IL-6阻断，最佳的总体反应率和毒性也显示出减少免疫相关的 免疫治疗的不良事件。西蒙两阶段设计试验将包括67名患者， 三重组合，并将由BMS支持。在这一建议中，我们希望支持相关的 基于该II期试验的标记物研究。将进行血清、肿瘤和外周血的分析 建立疗效和毒性的生物标志物，并帮助了解对联合用药耐药的基础。 ICB在黑色素瘤中基于三个特定目的：1.确定基线水平或治疗期间是否发生变化 在血清质谱-MALDI-TOF蛋白特征和急性期反应物和细胞因子中， 与IL-6受体阻断抗体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细胞的基线或治疗期间变化 通过多参数流式细胞术、Ab-Seq和IsoLight测定、外周血 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序列 在使用托珠单抗的IPI/NIVO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，以评估是否存在巩固的 在一项使用托珠单抗的IPI/NIVO II期研究中，特征与反应和毒性相关。

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.