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

基本信息

批准号：
9916443
负责人：
Ann Richmond
金额：
$ 37.65万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/9916443
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 Expression Profiling 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 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 Xenograft Model Xenograft procedure angiogenesis 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/antagonist lymph nodes malignant breast neoplasm melanoma men mouse model mutant neoplastic cell outcome forecast 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

项目摘要

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) 是全球约 40,610 名女性和 460 名女性的主要健康问题。仅美国男性预计今年就会死于乳腺癌，而激素治疗方案有多种。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治疗转移性 BC 的改进选择代表了巨大的最近，一些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 通路在然而，超过 50% 的 BC 患者的无进展生存期仅延长了 2-4 个月。免疫检查点的发现存在广泛的3级和4级毒性剂量。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为了验证这一假设，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的异种移植物（PDX）的人源化小鼠模型确定 PI3K 通路抑制剂是否能增强对 ICI 的反应并提高小鼠的存活率有两种。具体目标 1. 制定通过 AKT 治疗减少 TNBC 生长的最佳策略。抑制剂 ipatasertib 联合紫杉醇和免疫检查点抑制剂 (ICIs) 抗 CTLA4 + 抗 PD1。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分析进行研究。以下参数：肿瘤生长；免疫细胞含量（免疫组）；肿瘤、骨髓、肺和血液样本中的表达谱以及反应中的转录组；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) 以及预测小鼠治疗反应的转录组学和免疫组学特征。与我们可获得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) 小鼠模型将具有遗传/免疫特征。进行评估并与正在进行的临床试验的数据进行比较。