Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway

优化乳腺癌免疫检查点抑制剂治疗的反应：PI3K 通路抑制剂的作用

• 批准号: 10305634
• 负责人: Ann Richmond
• 金额: $ 35.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-11 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305634
• 关键词: AKT inhibition; Autoimmunity; Blood specimen; Bone Marrow; Breast Cancer Model; Breast Cancer Patient; Breast Cancer therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cell Death; Cells; Chemotherapy and/or radiation; Clinical Research; Clinical Trials; Coculture Techniques; Combined Modality Therapy; DNA sequencing; Data; Dose; Dose-Limiting; ERBB2 gene; Endothelial Cells; Environment; Exhibits; Fibroblasts; Flow Cytometry; Future; Genetic; Growth; Health; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunohistochemistry; Immunologics; Immunotherapy; Infiltration; Inflammation; Leukocytes; Link; Lung; Mammary Neoplasms; Mediating; Mediator of activation protein; Medical; Metastatic breast cancer; Microtubules; Modeling; Mus; Mutate; Mutation; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oncogenes; Organoids; Paclitaxel; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Poison; Prediction of Response to Therapy; Prognosis; Progression-Free Survivals; Property; Protein Analysis; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Regulatory T-Lymphocyte; Relapse; Role; Schedule; Stromal Cells; Stromal Neoplasm; Survival Rate; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Tumor-infiltrating immune cells; Woman; angiogenesis; antagonist; anti-CTLA4; anti-PD-1; anti-tumor immune response; base; breast cancer survival; cancer therapy; checkpoint therapy; chemokine; cytokine; design; dosage; early phase clinical trial; effector T cell; genetic signature; hormone receptor-positive; humanized mouse; immune checkpoint; immunogenic; immunogenic cell death; improved; inhibitor; inhibitor therapy; lymph nodes; malignant breast neoplasm; melanoma; men; mouse model; mutant; neoplastic cell; patient derived xenograft model; predicting response; predictive signature; programmed cell death ligand 1; programmed cell death protein 1; response; standard of care; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor-immune system interactions

Metastatic breast cancer (BC) is a major health issue for women across the world. About 40,610 women and 460 men in the US are expected to die this year alone from BC. While there are numerous treatment options for hormone receptor positive (HR+) and HER2+ BC patients, the standard of care for triple negative BC (TNBC) patients largely relies on conventional chemotherapy and radiation. Improved options for treating metastatic BC represent a vast unmet medical need. Recently, several clinical trials investigated combined treatment with either HR pathway blockers or HER2 antagonists and PI3K inhibitors, since the PI3K pathway is constitutively activated or mutated in over 50% of BC patients. However, the results have shown only 2-4 months increase in progression free survival and there is extensive Grade 3 and 4 toxicity with the dosage schedules used. The discovery of immune checkpoint inhibitors (ICIs) is revolutionizing cancer therapy, but thus far BC patients are not showing strong responses to ICI therapy, due to low mutational load and minimal infiltration of CD4+ and CD8+ T cells (“cold”). Our hypothesis is that response to ICI therapy in immunologically “cold” BCs can be enhanced by combining therapies that inhibit AKT with paclitaxel (PTX) to induce immunogenic tumor cell death and shift tumor-associated immune cells to an anti-tumor phenotype. To test this hypothesis, we will utilize immune competent mouse models, organoid/immune cell co-cultures, and humanized mouse models bearing patient-derived xenograft (PDX) to determine if PI3K pathway inhibitors, when enhance response to ICIs, and improve survival in mice. There are two specific aims. Aim 1. To develop the optimal strategy for reducing growth of TNBC through treatment with an AKT inhibitor, ipatasertib, combined with paclitaxel, and immune checkpoint inhibitors (ICIs) anti-CTLA4 + anti-PD1. Using immune competent mouse models, we will determine the functional significance of reprograming the tumor immune environment in mammary tumors in response to AKT inhibition in reference to response to ICIs at early, mid and late time points during therapy. Mechanisms of therapeutic response will be investigated based upon analysis of the following parameters: toxicity; tumor growth; metastasis; immune cell content (immunome); cytokine/chemokine expression profile in tumor, bone marrow, lung and blood samples; angiogenesis; and transcriptome in responding and non- responding tumors. State of the art technology will include multiplex immunohistochemistry (IHC), flow cytometry, CyTOF, reverse phase protein analysis (RPPA), RNA sequencing (RNAseq), DNA sequencing (DNAseq) and pathway analysis. Transcriptomic and immunome signatures predicting response to treatment in mice will be compared to RNAseq data from ongoing clinical trials available to us and published “response signatures” 26. Aim 2: To determine the efficacy of treatment with AKT inhibitors combined with PTX and ICIs in two human TNBC models: 1) organoid co-cultures human TNBC plus fibroblasts, endothelial cells and patient immune cells: 2) humanized patient-derived xenografts (PDX) mouse models established from TNBC patients. Genetic/immunome signatures will be evaluated and compared to data from ongoing clinical trials.

转移性乳腺癌（BC）是全世界女性的一个主要健康问题。约 40,610 名女性和 460 名 仅今年，美国男性预计就会死于不列颠哥伦比亚省。虽然激素治疗有多种选择 受体阳性 (HR+) 和 HER2+ BC 患者，三阴性 BC (TNBC) 患者的护理标准主要是 依赖常规化疗和放疗。治疗转移性 BC 的改进选择代表了巨大的 未满足的医疗需求。最近，多项临床试验研究了与任一 HR 途径的联合治疗 阻断剂或 HER2 拮抗剂和 PI3K 抑制剂，因为 PI3K 通路在 超过 50% 的 BC 患者。然而，结果显示无进展生存期仅增加 2-4 个月，并且 使用的剂量方案存在广泛的 3 级和 4 级毒性。免疫检查点的发现 抑制剂 (ICIs) 正在彻底改变癌症治疗，但迄今为止 BC 患者并未对 ICI 表现出强烈的反应 治疗，由于突变负荷低且 CD4+ 和 CD8+ T 细胞浸润极少（“冷”）。 我们的假设是，通过结合以下方法可以增强免疫“冷”BC 对 ICI 治疗的反应： 使用紫杉醇 (PTX) 抑制 AKT 的疗法可诱导免疫原性肿瘤细胞死亡并改变肿瘤相关性 免疫细胞具有抗肿瘤表型。为了检验这个假设，我们将利用具有免疫能力的小鼠模型， 类器官/免疫细胞共培养物以及携带患者来源异种移植物（PDX）的人源化小鼠模型 确定 PI3K 通路抑制剂是否可以增强对 ICI 的反应并提高小鼠的存活率。有两个 具体目标。目标 1. 制定通过 AKT 治疗减少 TNBC 生长的最佳策略 抑制剂，ipatasertib，与紫杉醇和免疫检查点抑制剂（ICIs）联合抗CTLA4+抗PD1。使用 免疫活性小鼠模型，我们将确定重新编程肿瘤免疫的功能意义 乳腺肿瘤环境对 AKT 抑制的反应，参考早期、中期和晚期对 ICI 的反应 治疗期间的时间点。将根据对治疗反应的分析来研究治疗反应的机制 以下参数：毒性；肿瘤生长；转移;免疫细胞含量（免疫组）；细胞因子/趋化因子 肿瘤、骨髓、肺和血液样本中的表达谱；血管生成；和转录组的反应 和无反应肿瘤。最先进的技术将包括多重免疫组织化学 (IHC)、流式细胞术 细胞计数、CyTOF、反相蛋白分析 (RPPA)、RNA 测序 (RNAseq)、DNA 测序 (DNAseq) 和路径分析。预测小鼠治疗反应的转录组学和免疫组学特征将是 与我们现有的正在进行的临床试验和已发布的“响应特征”的 RNAseq 数据进行比较 26. 目标 2： 为了确定 AKT 抑制剂联合 PTX 和 ICI 在两种人类 TNBC 模型中的治疗效果： 1) 类器官共培养人 TNBC 加成纤维细胞、内皮细胞和患者免疫细胞：2) 人源化 从 TNBC 患者建立的患者来源的异种移植 (PDX) 小鼠模型。遗传/免疫特征将 进行评估并与正在进行的临床试验的数据进行比较。