Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment

纳米免疫药物靶向肿瘤微环境治疗神经胶质瘤

基本信息

批准号：
10743942
负责人：
Alexander V Ljubimov
金额：
$ 57.7万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10743942
关键词：
Acids Acute Adaptive Immune System Affect Animals Antibodies Biochemical Bioinformatics Biological Assay Blood Blood - brain barrier anatomy Brain Brain Neoplasms CRISPR/Cas technology Cancer Intervention Cancer Patient Cell membrane Cells Clinical Clinical Data Clinical Trials Collaborations Cytometry DNA Sequence Alteration Data Development Drug Delivery Systems Endothelial Cells Epidermal Growth Factor Receptor Evaluation Extracellular Matrix Proteins Female Gene Expression Generations Genes Glioblastoma Glioma Growth Human Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Markers Immunologic Surveillance Immunotherapy In Vitro Innate Immune System Intervention Intravenous Invaded Laboratories Laminin Lead Macaca fascicularis Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Molecular Target Mus Nanotechnology Neoplasm Metastasis No-Observed-Adverse-Effect Level Organ Oryctolagus cuniculus Pathologic Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Polymers Population Primary Brain Neoplasms Primates Production Prognosis Proliferating Proteins Protocols documentation Radiation Radiation therapy Recurrence Relapse Sampling System TFAP2A gene Technology Testing Therapeutic Uses Therapeutic antibodies Time Toxic effect Toxicology Translational Research Translations Treatment Efficacy Up-Regulation Variant anti-CTLA4 anti-CTLA4 antibodies anti-PD-1 anti-PD1 antibodies blood-brain barrier crossing c-myc Genes cancer cell cancer therapy clinically relevant dosage drug development drug production drug testing effective therapy endosome membrane immune checkpoint in vivo male molecular marker mouse model nano nanodrug nanomedicine nanopolymer nanotechnology platform neoplastic cell notch protein novel novel strategies overexpression pharmacologic precision drugs programmed cell death protein 1 scale up single-cell RNA sequencing small molecule standard of care temozolomide therapeutic RNA transcriptome sequencing translational study tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Glioblastoma (GBM) is the most lethal form of brain cancer. Treatment options are limited, in part because of inefficient drug delivery across the blood-brain barrier (BBB). GBM microenvironment contributes to malignant growth, invasion, and escape from immune surveillance. We will develop a radically new strategy of GBM treatment by simultaneous targeting of tumor microenvironment and activating brain cancer privileged immune system. This new combination approach aims to regulate tumor microenvironment components that are largely independent of heterogeneous genetic mutations in glioblastoma. It has potential advantage over conventional GBM treatment with small molecule drugs, radiation and targeted molecular marker(s) inhibition. In the frame of the FOA "Toward Translation of Cancer Nanotechnology Interventions", we will develop the translation of cancer interventions using novel nanomedicines able to cross biobarriers, such as BBB, cell and endosomal membranes, and modulate tumor microenvironment for effective therapy that may treat not only brain primary tumors (GBM) but other poorly treatable brain secondary/metastatic tumors. We plan to understand the interactions between extracellular matrix (ECM) protein laminin-411 (a4b1g1) expression and brain local immune system as parts of GBM-promoting immunosuppressive microenvironment. Our clinical data on 130 GBM patients showed that tumor laminin-411 correlated with tumor aggressiveness, poor patient survival and early recurrence. We developed nano drugs based on natural polymer, poly(β-L-malic acid), able to block the synthesis of trimer protein laminin-411 in vivo. We also used syngeneic mouse models treated with nano immuno drugs delivering to GBM checkpoint inhibitor antibodies anti-CTLA-4 or anti-PD-1 that in free form do not cross BBB, which increased animal survival. Nanodrugs were well characterized and non- toxic in mice and rabbits (collaboration with Nanotechnology Characterization Laboratory). Nano polymeric drugs production was scaled up to grams. Toxicity and PK studies were successfully performed on primates, male/female Cynomolgus macaques using therapeutic 1X and acute 10X intravenous dosages. We also developed a nano immuno delivery system on the same platform bearing anti-CTLA-4 or anti-PD-1 antibodies that traversed BBB, activated local brain immune system and prolonged animal survival. New preliminary data demonstrate that laminin-411 regulates Notch pathway and activation of NK, NKT, IFNg+ NKT, and macrophages, whereas checkpoint inhibitors delivered to the brain on nanoplatform regulate both innate and adaptive immune system. Our translational research is geared towards developing clinically suitable combinations of BBB-crossing nanomedicines for efficient glioma treatment. Aim 1. Synthesis of novel nano drug variants for combination brain cancer therapy. Aim 2. Lead nano drug testing for glioma treatment efficacy. Aim 3. Pharmacological (PK, PD) and toxicological examination of lead nano immunopolymers.

胶质母细胞瘤（GBM）是脑癌最致命的形式。治疗选择是有限的，部分是因为在整个血脑屏障（BBB）上递送的药物效率低下。 GBM微环境有助于恶性生长，入侵和免疫监测。我们将制定GBM的根本新策略通过简单靶向肿瘤微环境和激活脑癌特权免疫治疗系统。这种新的组合方法旨在调节很大程度上的肿瘤微环境组件独立于胶质母细胞瘤中的异质基因突变。它比传统具有潜在的优势 GBM用小分子药物，辐射和靶向分子标记（S）抑制作用。框架 FOA“向癌症纳米技术干预措施翻译”，我们将发展癌症的翻译使用新型纳米药物可以跨越生物载体的干预措施，例如BBB，细胞和内体膜，并调节肿瘤微环境进行有效治疗，不仅可以治疗脑肿瘤（GBM）但是其他无法治疗的大脑继发/转移性肿瘤。我们计划了解细胞外基质（ECM）蛋白层粘连蛋白-411（A4B1G1）之间的相互作用表达和大脑局部免疫抑制微环境作为GBM促进免疫抑制微环境的一部分。我们对130名GBM患者的临床数据表明，肿瘤层粘连蛋白411与肿瘤侵袭性相关，患者的生存不良和早期复发。我们开发了基于天然聚合物poly（β-l-malic）的纳米药物酸），能够阻止体内三聚体蛋白层粘连蛋白411的合成。我们还使用了同烯鼠标模型用纳米免疫药物治疗的纳米免疫药物递送给GBM检查点抑制剂抗体抗CTLA-4或抗PD-1 自由形式不要越过BBB，这会增加动物的存活率。纳米果的特征是且非 - 在小鼠和兔子中有毒（与纳米技术表征实验室合作）。纳米聚合药生产扩展到克。毒性和PK研究成功地对私人进行了雄性/雌性cynomolgus猕猴使用治疗1倍和急性10倍静脉注射剂量。我们还在带有抗CTLA-4或抗PD-1的同一平台上开发了纳米免疫输送系统遍历BBB，激活局部脑免疫系统并延长动物存活的抗体。新的初步数据表明，层粘连蛋白411调节NK，NKT，IFNG+ NKT的凹槽途径和激活和巨噬细胞，而检查点抑制剂在纳米板上传递到大脑，调节两个先天性和自适应免疫学系统。我们的翻译研究旨在开发临床上适当的 BBB跨纳米药物的组合进行有效的神经胶质瘤治疗。 AIM 1。新型纳米药物变异的合成脑癌疗法。目标2。铅纳米药物测试用于神经胶质瘤治疗效率。 AIM 3。药理学（PK，PD）和铅Nano的毒理学检查免疫聚合物。