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: 10531596
• 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/10531596
• 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; Macrophage; Mammary Neoplasms; Mediating; Mediator; Medical; Metastatic breast cancer; Microtubules; Mus; Mutate; Mutation; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oncogenes; Organoids; PIK3CG gene; 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; Woman; angiogenesis; antagonist; anti-CTLA4; anti-PD-1; anti-tumor immune response; breast cancer survival; cancer therapy; checkpoint therapy; chemokine; cytokine; design; dosage; early phase clinical trial; effector T cell; efficacy evaluation; genetic signature; hormone receptor-positive; humanized mouse; immune cell infiltrate; 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; phosphatidylinositol 3-kinase gamma; predicting response; predictive signature; programmed cell death ligand 1; programmed cell death protein 1; response; standard of care; synergism; 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)是世界各地女性的主要健康问题。约40,610名女性和460名 预计仅今年一年，美国就会有男性死于公元前。虽然有许多激素的治疗选择 受体阳性(HR+)和HER2+BC患者，三阴性BC(TNBC)患者的标准护理 依靠传统的化疗和放射治疗。治疗转移性结直肠癌的改进方案代表着巨大的 未得到满足的医疗需求。最近，几项临床试验研究了HR途径或HR途径的联合治疗 阻滞剂或HER2拮抗剂和PI3K抑制剂，因为PI3K途径在 超过50%的BC患者。然而，结果显示，仅有2-4个月的无进展存活率和 所使用的剂量表有广泛的3级和4级毒性。免疫检查点的发现 抑制剂(ICIS)正在给癌症治疗带来革命性的变化，但到目前为止，BC患者对ICI并没有表现出强烈的反应 治疗，由于低突变负荷和最低限度的CD4+和CD8+T细胞的渗透(“冷”)。 我们的假设是，免疫“冷”BCS对ICI治疗的反应可以通过联合 用紫杉醇(PTX)抑制AKT诱导免疫原性肿瘤细胞死亡和转移肿瘤相关性的治疗 免疫细胞的一种抗肿瘤表型。为了验证这一假设，我们将利用免疫能力强的小鼠模型， 器官/免疫细胞共培养，以及携带患者来源的异种移植(PDX)的人源化小鼠模型 确定PI3K通路抑制剂在增强对ICIS的反应并改善小鼠的存活率时是否具有这种作用。有两个 明确的目标。目的1.通过AKT治疗寻找减少TNBC生长的最佳策略 抑制剂，ipatasertib，与紫杉醇联合，以及免疫检查点抑制物(ICIS)抗CTLA4+抗PD1。vbl.使用 免疫活性小鼠模型的建立，我们将确定重编肿瘤免疫程序的功能意义 早期、中期和晚期乳腺肿瘤环境对AKT抑制的反应与对ICIS的反应 治疗期间的时间点。治疗反应的机制将根据对 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、肺和血液样本的表达谱；血管生成；以及反应中的转录组 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)、Flow 细胞学、细胞周期、反相蛋白分析(RPPA)、RNA测序(RNAseq)、DNA测序(DNAseq) 和通径分析。在小鼠中预测治疗反应的转录和免疫组学特征将是 与RNAseq数据相比，RNAseq数据来自我们可用的正在进行的临床试验和公布的“响应签名”26。目标2： 为了确定AKT抑制剂联合PTX和ICIS在两种人TNBC模型中的治疗效果： 1)人TNBC与成纤维细胞、内皮细胞和患者免疫细胞的有机共培养：2)人源化 从TNBC患者建立患者来源的异种移植(PDX)小鼠模型。基因/免疫组签名将 进行评估，并与正在进行的临床试验的数据进行比较。