Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao)

项目3 - 靶向CDK4/6调节胶质瘤的免疫原性（Wen/Zhao）

基本信息

批准号：
10696102
负责人：
Jean Zhao
金额：
$ 30.35万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10696102
关键词：
Adult Affect Aftercare Antigen Presentation Antigen Presentation Pathway Basic Science Blood Blood specimen Brain Breast Carcinoma CD8-Positive T-Lymphocytes CD8B1 gene CDK4 gene CDKN2A gene CTLA4 gene Cell Cycle Arrest Cell Cycle Progression Cell Line Cells Central Nervous System Cephalic Clinical Clinical Data Clinical Sciences Clinical Trials Clinical Trials Design Clinical effectiveness Combined Modality Therapy Cyclin D1 Cytotoxic T-Lymphocytes Dana-Farber Cancer Institute Data Elements Environment Epidermal Growth Factor Receptor Estrogen Therapy Estrogen receptor positive FDA approved Face Future Genetic Genetic Annotation Genomics Glioblastoma Glioma Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologics Immunotherapy Malignant neoplasm of brain Mammary Neoplasms Mediating Metastatic breast cancer Microglia Modeling Molecular Molecular Abnormality Monitor Morbidity - disease rate Mus Mutation Neurosphere Newly Diagnosed Outcome PD-1 blockade PTEN gene Pathology Pathway interactions Patients Peptide Vaccines Pharmaceutical Preparations Phosphorylation Pre-Clinical Model Prognosis Progression-Free Survivals Proliferating Protocols documentation RB1 gene Recurrence Regulatory T-Lymphocyte Research Personnel Retinoblastoma Retinoblastoma Protein SCID Mice Sampling Scientist Signal Transduction Site Testing Therapeutic Tumor Immunity Work Xenograft procedure antagonist anti-tumor immune response cytotoxic design effective therapy experience genetic information immune checkpoint blockade immune function immunogenicity immunoreactivity improved ineffective therapies inhibitor malignant breast neoplasm mortality mouse model neoantigens neoplastic cell novel pembrolizumab phase II trial pre-clinical preclinical efficacy programmed cell death protein 1 programs receptor response synergism targeted treatment therapy outcome treatment strategy tumor tumor growth tumor-immune system interactions

项目摘要

Glioblastoma (GBM), the most common primary malignant brain tumor of adults, is a significant cause of patient morbidity and mortality for which effective treatments are lacking. The cyclin D1-cyclin dependent kinase 4/6-retinoblastoma (cyclinD1-CDK4/6-Rb) signaling axis is genetically activated in majority of GBM (~80%) via genomic loss of CDKN2A/B, amplification of CDK4/6 or deletion/mutation of RB1. CDK4/6 has been targeted based on the notion that suppressing the phosphorylation of pRB by CDK4/6 will lead to cell cycle arrest. Beyond suppressing cell cycle progression, we recently found that CDK4/6 antagonists promote anti-tumor immunity. The molecular mechanisms underlying this are exerted at two levels: (i) a tumor cellautonomous enhancement of the antigen processing and presentation machinery and (ii) a non-tumor cellautonomous, systemic decrease of the Treg/CD8+ ratio. Collectively, these effects promote cytotoxic T cellmediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade therapeutics. Notably the actions of the combination of CDK4/6 inhibition and checkpoint blockade was much greater than additive in our preclinical models. CDK4/6 inhibitors are FDA-approved for the treatment of estrogen receptor (ER)-positive metastatic breast cancer, where they now present a well-tolerated, first-line therapy that improves progression-free survival. Their efficacy against GBM is unknown. However, early unpublished clinical data suggest that, like most targeted therapies, CDK4/6 inhibitors as single agents may have only modest benefit. Similarly, early data on immune checkpoint blockade have not been promising in recurrent GBM in which recently this class of drug failed to improve survival as single agent therapy. Building upon our recent findings, we hypothesize that brain penetrant CDK4/6 inhibitors could augment immunotherapy approaches for GBM including PD-1 checkpoint inhibitors for recurrent GBM. This proposal has three specific aims designed to investigate the therapeutic approach of combined CDK4/6 inhibition and immune checkpoint blockade (ICB) in GBM in both preclinical and clinical settings: (Aim 1) To assess the effects of CDK4/6 inhibition on GBM cell-intrinsic immune response; (Aim 2) To assess the effects of CDK4/6 inhibition on enhancing immunotherapy in syngeneic models of GBM; and (Aim 3) To evaluate the impact of CDK4/6 inhibitors on immune function and clinical outcome for GBM patients. By using patient-derived GBM tumors and syngeneic mouse models of GBM, we will determine the preclinical efficacy of CDK4/6 inhibitors in combination with immunotherapy against GBM, further solidifying the preclinical rationale to design clinical trials for patients with GBM.

胶质母细胞瘤（GBM）是成人最常见的原发性恶性脑肿瘤，是导致缺乏有效治疗的患者发病率和死亡率。细胞周期蛋白 D1 依赖于细胞周期蛋白激酶 4/6-视网膜母细胞瘤 (cyclinD1-CDK4/6-Rb) 信号轴在大多数 GBM 中被基因激活 (~80%) 通过 CDKN2A/B 的基因组丢失、CDK4/6 的扩增或 RB1 的缺失/突变。 CDK4/6有基于 CDK4/6 抑制 pRB 磷酸化将导致细胞循环逮捕。除了抑制细胞周期进程外，我们最近发现 CDK4/6 拮抗剂还促进抗肿瘤免疫力。其背后的分子机制在两个层面上发挥作用：（i）肿瘤细胞自主增强抗原加工和呈递机制，以及（ii）非肿瘤细胞自主、 Treg/CD8+ 比率的系统性降低。总的来说，这些作用促进了细胞毒性 T 细胞介导的肿瘤细胞的清除，通过添加免疫检查点阻断进一步增强疗法。值得注意的是，CDK4/6 抑制和检查点阻断相结合的作用显着增加。在我们的临床前模型中大于添加剂。 CDK4/6 抑制剂已获得 FDA 批准用于治疗雌激素受体（ER）阳性的转移性乳腺癌，它们现在是一种耐受性良好的一线药物改善无进展生存期的治疗。它们对 GBM 的功效尚不清楚。然而，早未发表的临床数据表明，与大多数靶向治疗一样，CDK4/6 抑制剂作为单一药物可能仅带来有限的好处。同样，关于免疫检查点封锁的早期数据也并不乐观。复发性 GBM，最近此类药物作为单药治疗未能提高生存率。建筑根据我们最近的发现，我们假设脑渗透性 CDK4/6 抑制剂可以增强 GBM 的免疫治疗方法包括治疗复发性 GBM 的 PD-1 检查点抑制剂。这个提议具有三个具体目标，旨在研究联合 CDK4/6 抑制的治疗方法和 GBM 中的免疫检查点阻断 (ICB) 在临床前和临床环境中：（目标 1）评估 CDK4/6 抑制对 GBM 细胞内在免疫反应的影响；（目标2）评估CDK4/6的效果对 GBM 同基因模型中增强免疫治疗的抑制；（目标 3）评估影响 CDK4/6 抑制剂对 GBM 患者免疫功能和临床结果的影响。通过使用患者来源的 GBM 肿瘤和 GBM 同基因小鼠模型，我们将确定 CDK4/6 抑制剂的临床前疗效与 GBM 免疫疗法相结合，进一步巩固设计临床的临床前理论基础 GBM 患者的试验。