Targeted MEK inhibition to enhance immunotherapy in cholangiocarcinoma

胆管细胞癌(CC)是一种对大多数化疗或靶向治疗无效的侵袭性癌症。 探员们。我们的目标是将免疫治疗的成功推广到CC，并确定与此相关的生物标志物 接近。这项建议将翻译临床前的研究结果，表明MEK抑制剂(Meki)增强了渗透 抑制CD8+T效应细胞，防止其彻底的细胞死亡，并增强抗PD-L1单抗的疗效。 肿瘤模型。我们假设Meki将与PD-L1阻滞剂协同作用，通过 改变细胞因子和趋化因子信号，促进CD8+T细胞的渗透和存活，并降低 肿瘤微环境(TME)中的免疫抑制细胞我们将进行创新的随机化 2期临床试验，以检查Meki(Cobimetinib)联合应用的安全性和有效性 PD-L1(阿替唑单抗)和阿替唑单抗治疗不能切除的CC患者。这场审判将是 在我们批准的NCI赞助的UM1临床试验拨款的背景下进行。同时进行的研究将 阐明Meki作用于T细胞和髓系细胞的机制，并增强PD-L1受体阻滞剂的疗效。 这项试验将提供来自可及性肿瘤患者的配对活检，在其中我们可以验证我们的机制 使用创新的多光谱成像的研究结果。这将是二线CC最大的临床研究。 我们将追求三个具体目标：1)进行PD-L1抑制剂的随机第二阶段临床试验 阿替唑单抗联合Meki cobimetinib与阿替唑单抗治疗 不能切除的CC。我们已通过NCI癌症治疗评估计划(CTEP)获得批准 在76名可评估的受试者中进行这项随机的多中心临床试验，这些受试者至少接受过一次 化疗。如果成功，这种方案有可能成为第二个CC的标准护理方案 排队。这项试验将提供样本来评估Meki对TME中关键生物标志物的影响。2)确定 Meki如何改变TME以提高对抗PD-L1治疗的反应。一组独特的人类CC细胞系 将用于研究Meki如何调节调节T细胞迁移的肿瘤衍生趋化因子。使用临床 我们将评估CD8+T细胞浸润和PD-L1表达作为综合生物标志物。多个- 光谱IHC将表征治疗对免疫亚群和穷竭性T细胞死亡标志物的影响 (即Nur77)在TME中的作用以及对免疫抑制T调节细胞和髓系来源的影响 抑制细胞。3)确定系统细胞因子和免疫细胞群在应对 梅基和PD-L1封锁。体内模型将测试Meki+抗PD-L1治疗的疗效是否依赖于 干扰素-，T细胞功能和趋化因子介导的转运的关键细胞因子调节因子。体外研究将定义 如果Meki改变肿瘤衍生细胞因子(如IL-6、GM-CSF)对肿瘤细胞分化或功能的影响 抑制性髓系细胞。最后，使用患者外周血样本，我们将确定 细胞因子表达和免疫细胞表型与临床预后的关系

Cholangiocarcinoma (CC) is an aggressive cancer that has been refractory to most chemotherapeutic or targeted agents. Our goal is to extend success of immunotherapy to CC, and identify relevant biomarkers for this approach. This proposal will translate pre-clinical findings showing that MEK inhibitors (MEKi) enhance infiltration of CD8+ T effector cells, prevent their exhaustive apoptotic cell death, and enhance efficacy of anti-PD-L1 Ab in tumor models. We hypothesize that MEKi will synergize with PD-L1 blockade to elicit anti-tumor responses via altering cytokine and chemokine signatures that promote CD8+ T cell infiltration and survival and decreased immunosuppressive cells in the tumor microenvironment (TME). We will conduct an innovative randomized phase 2 clinical trial to examine safety and efficacy of a MEKi (cobimetinib) in combination with an inhibitor of PD-L1 (atezolizumab) and atezolizumab monotherapy in patients with unresectable CC. This trial will be performed in the context of our approved NCI-sponsored UM1 clinical trials grant. Concurrent studies will elucidate the mechanism by which MEKi acts on T and myeloid cells, and augments efficacy of PD-L1 blockade. The trial will provide paired biopsies from patients with accessible tumor in which we can validate our mechanistic findings using innovative multi-spectral imaging. This will be the largest clinical study of CC in the second line. We will pursue three Specific Aims: 1) To conduct a randomized phase 2 clinical trial of the PD-L1 inhibitor atezolizumab in combination with the MEKi cobimetinib versus atezolizumab monotherapy in participants with unresectable CC. We have completed approval through the NCI Cancer Therapy Evaluation Program (CTEP) to conduct this randomized, multicenter clinical trial in 76 evaluable subjects who have received at least one prior chemotherapy. If successful, this regimen has potential to become the standard of care for CC in the second line. This trial will provide samples to evaluate the effect of MEKi on key biomarkers in the TME. 2) To determine how MEKi alter the TME to improve the response to anti-PD-L1 therapy. A unique panel of human CC cell lines will be used study how MEKi modulates tumor-derived chemokines that regulate T cell migration. Using clinical trial biopsies, we will evaluate CD8+ T cell infiltration and PD-L1 expression as integrated biomarkers. Multi- spectral IHC will characterize the impact of treatment on immune subsets and markers of exhaustive T cell death (i.e. Nur77) in the TME as well as the impact on immunosuppressive T regulatory cells and myeloid-derived suppressor cells. 3) To determine the role of systemic cytokines and immune cell populations in the response to MEKi and PD-L1 blockade. In vivo models will test if the efficacy of MEKi + anti-PD-L1 therapy is dependent on IFN-, a key cytokine regulator of T cell function and chemokine-mediated trafficking. In vitro studies will define if MEKi alters the impact of tumor-derived cytokines (e.g. IL-6, GM-CSF) on differentiation or function of suppressive myeloid cells. Finally, using patient peripheral blood samples we will determine the relevance of relationships between cytokine expression and various immune cell phenotype with clinical outcome.