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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：
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
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/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

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）是全世界妇女的一个主要健康问题。大约有40610名女性和460名