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：
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
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/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

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）是全世界女性的主要健康问题。约40,610名女性和460名预计美国的男人将仅今年就死于卑诗省。虽然有很多人的治疗选择接收器阳性（HR+）和HER2+ BC患者，三重阴性BC（TNBC）患者的护理标准在很大程度上依赖于常规的化学疗法和放射线。改进的治疗转移性BC的选择代表了差距未满足的医疗需求。最近，一些临床试验研究了通过任何HR途径的合并治疗由于PI3K途径在组成式激活或突变中，因此阻滞剂或HER2拮抗剂和PI3K抑制剂超过50％的卑诗省患者。但是，结果仅显示出2-4个月的无进展生存率增加，并且使用剂量时间表的3级和4级毒性。免疫检查站的发现抑制剂（ICIS）正在彻底改变癌症治疗，但到目前为止，BC患者对ICI的反应很强治疗，由于CD4+和CD8+ T细胞的突变负荷低以及最小的浸润（“冷”）。我们的假设是，可以通过组合可以增强对免疫学上“冷” BC中对ICI治疗的反应用紫杉醇（PTX）抑制AKT的疗法诱导免疫原性细胞死亡并移动肿瘤相关免疫细胞对抗肿瘤表型。为了检验该假设，我们将利用免疫胜任的小鼠模型，器官/免疫细胞共培养以及带有患者衍生Xenographographic（PDX）的人源化小鼠模型确定PI3K途径抑制剂是否会增强对ICI的反应并改善小鼠的存活率。有两个具体目标。目标1。制定通过AKT治疗来减少TNBC增长的最佳策略抑制剂ipatasertib与紫杉醇和免疫切解点抑制剂（ICIS）抗CTLA4 +抗PD1结合使用。使用免疫胜任的小鼠模型，我们将确定重编程肿瘤免疫的功能意义乳腺肿瘤的环境响应于Akt抑制作用，参考早期，中期和晚期对ICI的反应治疗过程中的时间点。将根据对治疗反应的机制进行研究以下参数：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；和响应中的转录组和无反应的肿瘤。最先进的技术将包括多重免疫组织化学（IHC），流量细胞仪，细胞术，反相蛋白分析（RPPA），RNA测序（RNASEQ），DNA测序（DNASEQ）（DNASEQ）和途径分析。可预测小鼠治疗反应的转录组和免疫组特征将是与正在进行的临床试验中的RNASEQ数据相比，我们可以提供的“响应签名” 26。目标2：为了确定用Akt抑制剂与PTX和ICIS在两个人类TNBC模型中结合的治疗效率： 1）类型培养物人类TNBC加上成纤维细胞，内皮细胞和患者免疫细胞：2）人性化由TNBC患者建立的患者衍生异种移植物（PDX）小鼠模型。遗传/免疫组特征将评估并与正在进行的临床试验的数据进行比较。