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

• 批准号: 9917700
• 负责人: JULIA Y LJUBIMOVA
• 金额: $ 57.03万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917700
• 关键词: Acids; Acute; Animals; Antibodies; Apoptosis; Binding; Biochemical; Biochemistry; Biodistribution; Biological Assay; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CTLA4 gene; Cell Proliferation; Cells; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Databases; Detection; Dose; Drug Kinetics; 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; No-Observed-Adverse-Effect Level; Nude Mice; Organ; Outcome; PD-1 blockade; 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; anti-CTLA4; anti-PD-1; anti-PD1 antibodies; anti-tumor immune response; base; blood-brain barrier crossing; cancer biomarkers; cancer cell; cancer immunotherapy; cancer therapy; casein kinase II; cytokine; drug action; epidermal growth factor receptor VIII; melanoma; molecular marker; monocyte; nano; nanocarrier; nanodrug; nanomedicine; novel; overexpression; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; public health relevance; receptor; receptor expression; systemic toxicity; targeted delivery; targeted treatment; tumor; tumor growth

 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（由申请人提供）：脑癌及其最常见的形式，多形性胶质母细胞瘤（GBM），平均生存期为15个月，治疗选择仍然有限。能够穿过血脑屏障（BBB）的有效纳米药物的出现为脑癌的新治疗带来了希望。我们将推出新一代纳米缀合物，可以穿过BBB并激活全身和局部脑肿瘤免疫系统;同时它们可以特异性阻断GBM分子标记物，从而显着提高荷瘤动物的生存率。初步数据显示，根据我们来自NIH/NCI癌症基因组图谱网络GBM联盟的Cell（2013）研究，GBM被阻断蛋白激酶CK 2和最常被GBM过表达的表皮生长因子受体（EGFR和EGFRvIII）的纳米缀合物有效抑制。针对细胞毒性T淋巴细胞（CTL）相关抗原4（CTLA-4）或针对淋巴细胞表面受体PD-1的抗体关闭抑制机制以允许CTL激活强大的抗肿瘤免疫应答。然而，抗体不能穿过BBB并调节脑癌免疫系统。基于初步数据，我们假设将这些抗体靶向纳米载体递送至局部肿瘤环境可以增强抗肿瘤免疫应答并降低这些疗法的全身毒性。我们将专门向脑肿瘤提供这种抗体，这些抗体附着在我们的纳米聚合物平台聚β-（L-苹果酸）上。将针对EGFR/EGFRvIII和CK 2的肿瘤靶向治疗与抗CTLA-4和/或抗PD-1的抗肿瘤免疫刺激相结合可以提供最深刻的GBM生长停滞。我们的假设是，基于癌症标志物的抑制与特异性免疫系统刺激相结合的靶向肿瘤抑制将增加BBB-交叉药物纳米缀合物对GBM的治疗功效。我们提出三个具体目标：1。新型纳米免疫结合物的合成及体外表征。将在培养的脑癌细胞中实现纳米缀合物的物理化学表征、合成的优化和所有部分的功能活性。2.纳米缀合物对脑肿瘤生长的抑制作用的检查。我们将使用BBB交叉纳米缀合物治疗裸鼠中的人GBM异种移植物（用于CK 2-EGFR组合）和免疫活性小鼠中的同基因脑肿瘤GL 26/GL 261（用于CTLA- 4和PD-1阻断）。全身性CTLA-4和PD-1抗体将用作对照。将选择铅纳米缀合物及其组合。3.纳米缀合物的药代动力学和毒理学研究。将在全身治疗后检查铅纳米缀合物的半衰期、生物分布和肿瘤靶向。确定最大耐受剂量的剂量递增研究将包括大体和显微病理学器官评价以及血液生化毒性。基于使用靶向纳米药物阻断特定肿瘤分子标记物的提案非常适合NCI精准医学计划。