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

项目摘要 尽管有几条证据支持在三阴性乳腺癌（TNBC）中使用免疫疗法， 在目前的临床试验中获得的适度的临床功效表明免疫抑制剂 PD-1/PD-L1阻断剂不能单独克服微环境的不良反应。为了改善结果，这 该项目将研究两种新兴的靶向乳腺癌治疗方法的免疫学效果，聚乙烯 （ADP-核糖）聚合酶（PARP）和BET布罗莫结构域（BBD）抑制剂，并将检验以下假设： 这些药物与免疫疗法的组合将是BRCA突变的有效治疗策略。 和散发性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 可以激活STING途径，改变色氨酸代谢并刺激 在临床前模型中，BBD抑制剂与紫杉醇和PD-L1阻断剂协同作用。 提出了两个具体目标。在目的1中，PARP抑制单独和与PD-1联合的作用 将在BRCA的动物模型中评估对免疫微环境和肿瘤生长的阻断， 相关的TNBC和临床试验。实验将在携带来源于TNBC的TNBC的小鼠中进行。 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 将定义病理完全缓解（pCR）率。临床前，PARP抑制和PD-1联合 还将在BRCA野生型同基因TNBC模型（包括EMT-6和JC）中研究阻断。在aim中 2中，将评估BBD抑制剂JQ1单独和与PD-L1阻断剂组合的作用。 与Aim 1以及临床试验中使用的TNBC的同基因和基因工程小鼠模型相同。 将评估免疫微环境组分的组成和活化的变化 在JQ1或JQ1和PD-L1治疗后，有或没有紫杉醇。最后，1期剂量递增试验 将JQ 1衍生物RO 6870810和atezolizumab组合为双联体，或与紫杉醇组合为三联体， 使用伴随和序贯时间表进行，其中将研究肿瘤活检以记录 免疫微环境以及编码PD-L1的CD274的拷贝数和表达的变化。的 该项目的成功完成将提高我们对这些目标免疫效应的了解 治疗，并可以确定生物标志物，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.