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：
10019491
负责人：
Jean Zhao
金额：
$ 35.88万
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/10019491
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 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 Deletion Mutation Elements Environment Epidermal Growth Factor Receptor Estrogen Therapy Estrogen receptor positive FDA approved Face Future Genetic 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 Neuraxis Newly Diagnosed Outcome PD-1 blockade PTEN gene Pathology Pathway interactions Patients Peptide Vaccines Pharmaceutical Preparations Phosphorylation Pre-Clinical Model Progression-Free Survivals 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 anti-tumor immune response base cytotoxic design effective therapy experience genetic information immune checkpoint blockade immune function immunogenicity immunoreactivity improved ineffective therapies inhibitor/antagonist malignant breast neoplasm mortality mouse model neoantigens neoplastic cell novel outcome forecast phase II trial pre-clinical preclinical efficacy programmed cell death protein 1 programs receptor response 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）是成年人最常见的原发性恶性脑肿瘤，是缺乏有效治疗的患者发病率和死亡率。细胞周期蛋白D1-循环依赖激酶4/6-雷诺母细胞瘤（Cyclind1-CDK4/6-Rb）信号轴在大多数GBM中都基因激活（〜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具有基于以下观点，即CDK4/6抑制PRB的磷酸化将导致细胞周期逮捕。除了抑制细胞周期的进展之外，我们最近发现CDK4/6拮抗剂促进抗肿瘤免疫。该层面的分子机制在两个级别上施加：（i）肿瘤大细胞自主增强抗原加工和表现机制以及（ii）非肿瘤的大提琴， Treg/CD8+比例的全身性降低。这些作用总体上促进了细胞毒性T细胞介导的肿瘤细胞的清除率，通过添加免疫检查点阻滞进一步增强疗法。值得注意的是，CDK4/6抑制和检查点封锁的组合的作用很大在我们的临床前模型中大于添加剂。 CDK4/6抑制剂是FDA批准的雌激素受体（ER） - 阳性转移性乳腺癌，现在它们呈现良好的一线改善无进展生存的治疗。他们对GBM的功效尚不清楚。但是，早未发表的临床数据表明，像大多数靶向疗法一样，CDK4/6抑制剂如单个药物可能只有适中的好处。同样，有关免疫检查点封锁的早期数据也不有希望复发性GBM最近，这类药物无法改善作为单药疗法的生存。建筑根据我们最近的发现，我们假设大脑渗透CDK4/6抑制剂可能会增加 GBM的免疫疗法方法，包括复发性GBM的PD-1检查点抑制剂。这个建议具有三个特定目的，旨在研究CDK4/6抑制合并的治疗方法临床前和临床环境中GBM中的免疫检查点封锁（ICB）：（目标1）评估 CDK4/6抑制对GBM细胞中性免疫反应的影响；（目标2）评估CDK4/6的影响抑制GBM的合成模型中增强免疫疗法的抑制作用；（目标3）评估 GBM患者对免疫功能和临床结果的CDK4/6抑制剂。通过使用患者来源的GBM GBM的肿瘤和合成小鼠模型，我们将确定CDK4/6抑制剂在结合针对GBM的免疫疗法，进一步巩固了设计临床的临床前原理 GBM患者的试验。