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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）是成人最常见的原发性恶性脑肿瘤，是导致脑癌的重要原因