Nanoconjugate delivery of proliferation and checkpoint inhibitors to treat glial tumors

纳米缀合物递送增殖和检查点抑制剂来治疗神经胶质瘤

基本信息

批准号：
9266719
负责人：
JULIA Y LJUBIMOVA
金额：
$ 54.91万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266719
关键词：
Acids Acute Animals Antibodies Apoptosis Binding Biochemical Biochemistry Biodistribution Biological Assay Blocking Antibodies Blood Blood - brain barrier anatomy Brain Brain Neoplasms Cell Proliferation Cells Clinical Treatment Clinical Trials Combined Modality Therapy Cytotoxic T-Lymphocyte-Associated Protein 4 Cytotoxic T-Lymphocytes Data Databases Detection Dose Drug Kinetics Drug effect disorder Environment Epidermal Growth Factor Receptor Evaluation Flow Cytometry Generations Glioblastoma Glioma Growth Half-Life Human Immune Immune checkpoint inhibitor Immune response Immune system Immunization Immunocompetent Immunoconjugates In Vitro Individual Lead Ligands Lymphocyte MAPK3 gene Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Modification Molecular Mus Mutate Names Nanoconjugate Nude Mice Organ Outcome PDCD1LG1 gene Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Phosphorylation Precision Medicine Initiative Protocols documentation Publishing Regulatory T-Lymphocyte Signal Transduction Specificity Stat5 protein Surface T-Cell Activation T-Lymphocyte TFRC gene Testing The Cancer Genome Atlas Therapeutic antibodies Time Toxic effect Toxicology Treatment Efficacy Treatment-related toxicity Tumor Immunity Tumor Suppression United States National Institutes of Health Variant Work Xenograft Model Xenograft procedure base cancer biomarkers cancer cell cancer immunotherapy cancer therapy casein kinase II cytokine epidermal growth factor receptor VIII melanoma molecular marker monocyte nano nanocarrier nanodrug nanomedicine novel overexpression peripheral blood public health relevance receptor receptor expression systemic toxicity targeted delivery targeted treatment tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Brain cancer, and its most common form, glioblastoma multiforme (GBM), with a 15-month average survival, still has limited treatment options. The emergence of efficacious nanodrugs able to cross blood-brain barrier (BBB) gives hope for new treatments of brain cancer. We will introduce new generation of nanoconjugates that pass through BBB and activate general and local brain tumor immune systems; at the same time they specifically block GBM molecular markers, which significantly increases survival of tumor-bearing animals. Preliminary data show that GBM are efficiently inhibited by nanoconjugates blocking protein kinase CK2, and epidermal growth factor receptor (EGFR and EGFRvIII) most frequently overexpressed by GBM per our Cell (2013) study from the NIH/NCI Cancer Genome Atlas Network GBM consortium. Antibodies to cytotoxic T lymphocyte (CTL)-associated antigen 4 (CTLA-4) or to lymphocytic surface receptor PD-1 turn off the inhibitory mechanism to allow CTL to activate powerful anti-tumor immune response. However, antibodies cannot cross the BBB and modulate brain cancer immune system. Based on preliminary data, we postulate that targeted nanocarrier delivery of such antibodies to local tumor environment could boost anti-tumor immune response and reduce systemic toxicity of these therapies. We will specifically deliver to brain tumors such antibodies attached to our nanopolymeric platform polyβ-(L-malic acid). Combining tumor targeted therapy against EGFR/EGFRvIII and CK2 with stimulation of anti-tumor immunity by anti-CTLA-4 and/or anti-PD-1 could provide the most profound GBM growth arrest. Our hypothesis is that targeted tumor suppression based on inhibition of cancer markers combined with specific immune system stimulation will increase the treatment efficacy of BBB-crossing drug nanoconjugates against GBM. We propose 3 specific Aims: 1. Synthesis and in vitro characterization of novel nano immunoconjugates. Physico-chemical characterization of nanoconjugates, optimization of synthesis, and functional activity of all moieties will be achieved in cultured brain cancer cells. 2. Examination of inhibitory effects f nanoconjugates on brain tumor growth. We will use BBB-crossing nanoconjugate treatment of human GBM xenografts in nude mice (for CK2-EGFR combination), and syngeneic brain tumors GL26/GL261 in immunocompetent mice (for CTLA- 4 and PD-1 blockade). Systemic CTLA-4 and PD-1 antibodies will serve as controls. Lead nanoconjugates and their combinations will be selected. 3. Pharmacokinetic and toxicological studies of nanoconjugates. Half- life, biodistribution, and tumor targeting of lead nanoconjugates will be examined upon systemic treatments. Dose escalating studies with maximum tolerated dose determination will include gross and micropathological organ evaluation and blood biochemistry for toxicity. The proposal based on specific tumor molecular marker blocking using targeted nanodrugs fits well NCI Precision Medicine Initiative.

描述（由申请人证明）：脑癌及其最常见的形式，胶质母细胞瘤多形（GBM），仍然具有有效的治疗选择。我们将通过BBB引入新的纳米缀合物，并激活一般和局部免疫系统。激酶CK2（EGFR和EGFRVIII）最常见于我们的细胞（2013）研究中最常表达从NIH/NCI癌症基因组基因组基因组网络GBM抗体抗体的细胞毒性T淋巴细胞（CTLA）或淋巴细胞表面受体PD-1旋转的NIH/NCI癌症基因组网络联盟抗体。 ISM允许CTL激活强大的抗肿瘤免疫反应。降低疗法的全身毒性。最深刻的GBM生长停滞增加了BB跨性别的药物对GBM的疗效。在培养的脑癌细胞中，所有Moietie的功能都将在培养的脑癌细胞中进行。纳米缀合物的药代动力学和毒理学研究。医学倡议。