Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer

项目总结 尽管有几条证据支持在三阴性乳腺癌(TNBC)中使用免疫疗法， 目前临床试验中取得的温和临床疗效表明，免疫抑制 单靠PD-1/PD-L1阻断不能克服微环境。为了改善结果，这一点 该项目将调查两种新兴的靶向乳腺癌治疗方法的免疫学效果，Poly (ADP-核糖)聚合酶(PARP)和BET溴域(BBD)抑制剂，并将检验以下假设 这些药物与免疫疗法的结合将成为BRCA突变的有效治疗策略 和零星的TNBC。这项工作的基本原理是基于我们的初步数据表明PARP抑制 能激活刺痛通路，改变色氨酸代谢，刺激细胞的渗透和激活 在临床前模型中，BBD抑制剂与紫杉醇和PD-L1拮抗剂具有协同作用。 提出了两个具体目标。在目标1中，单独抑制PARP和与PD-1联合使用的效果 对免疫微环境和肿瘤生长的阻断将在BRCA的动物模型中进行评估。 相关的TNBC和临床试验中。实验将在携带TNBCs的小鼠身上进行，TNBCs来源于 K14Cre；BRCA1f/f；p53f/f基因工程小鼠模型，并将在 使用niraparib或niraparib/PD-1联合治疗的新辅助治疗，其中T细胞浸润和 将定义病理完全应答(PCR)率。临床前联合应用PARP抑制和PD-1 Blockade还将在BRCA野生型同基因TNBC模型中进行研究，包括EMT-6和JC。在AIM 2、BBD抑制剂JQ1单独以及与PD-L1阻断联合使用的效果将在 AIM 1以及临床试验中使用的相同的同基因和基因工程的TNBC小鼠模型。 将评估免疫微环境成分的组成和激活的变化。 在JQ1或JQ1和PD-L1治疗后，加或不加紫杉醇。最后，一期剂量递增试验 将JQ1衍生物RO6870810和阿替唑单抗组合为二联体，或与紫杉醇组合为三联体，将是 使用相伴的和顺序的时间表进行，其中将研究肿瘤活检以记录 免疫微环境和编码PD-L1的CD274的拷贝数和表达的变化。这个 这个项目的成功完成将提高我们对这些靶向免疫效果的理解 治疗，并可能确定生物标志物，以帮助选择最有可能受益的患者。

PROJECT SUMMARY Although several lines of evidence support the use of immunotherapy in triple-negative breast cancer (TNBC), the modest clinical efficacy achieved in current clinical trials suggests that the immunosuppressive microenvironment cannot be overcome by PD-1/PD-L1 blockade alone. In order to improve outcomes, this project will investigate the immunologic effects of two emerging classes of targeted breast cancer therapies, poly (ADP-ribose) polymerase (PARP) and BET bromodomain (BBD) inhibitors, and will test the hypothesis that combinations of these agents with immunotherapies will be effective therapeutic strategies for BRCA-mutated and sporadic TNBC. The rationale for this work is based on our preliminary data indicating that PARP inhibition can activate the STING pathway, alter tryptophan metabolism and stimulate the infiltration and activation of cytotoxic T cells, and that BBD inhibitors synergize with paclitaxel and PD-L1 blockade in preclinical models. Two specific aims are proposed. In Aim 1, the effects of PARP inhibition alone and in combination with PD-1 blockade on the immune microenvironment and on tumor growth will be assessed in an animal model of BRCA- associated TNBC and in a clinical trial. Experiments will be conducted in mice bearing TNBCs derived from the K14Cre;BRCA1f/f;p53f/f genetically-engineered mouse model, and will translate to a phase 2 trial in the neoadjuvant setting using niraparib or combined niraparib/PD-1 therapy, in which changes in T cell infiltrate and pathologic complete response (pCR) rate will be defined. Preclinically, combined PARP inhibition and PD-1 blockade will also be investigated in BRCA wild-type syngeneic TNBC models, including EMT-6 and JC. In Aim 2, the effects of the BBD inhibitor JQ1 alone and in combination with PD-L1 blockade will be evaluated in the same syngeneic and genetically-engineered mouse models of TNBC used in Aim 1, as well as in a clinical trial. Changes in the composition and activation of components of the immune microenvironment will be assessed following JQ1 or JQ1 and PD-L1 treatment, with or without paclitaxel. Finally, a Phase 1 dose-escalation trial combining the JQ1 derivative RO6870810 and atezolizumab as a doublet, or with paclitaxel as a triplet, will be performed using concomitant and sequential schedules, in which tumor biopsies will be studied to document changes in the immune microenvironment and in copy number and expression of CD274, encoding PD-L1. The successful completion of this project will improve our understanding of the immune effects of these targeted therapies and may identify biomarkers to aid the selection of patients most likely to benefit.