Therapy for leptomeningeal medulloblastoma by a novel implantable pump

新型植入泵治疗软脑膜髓母细胞瘤

• 批准号: 8840675
• 负责人: ANAT ERDREICH-EPSTEIN
• 金额: $ 22.93万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840675
• 关键词: Activated Natural Killer Cell; Adult; Affect; Area; Blood - brain barrier anatomy; Brain; Categories; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Child; Clinical; Clinical Data; Clinical Trials; Data; Diagnosis; Disease; Dose; Drug Delivery Systems; Frequencies; Goals; Health; Human; Immune; Immunotherapy; Implant; Implantable Pump; In complete remission; Infusion procedures; Intravenous; Intraventricular; Label; Leptomeninges; Luciferases; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Metastatic Neoplasm to the Leptomeninges; Modeling; Monoclonal Antibodies; Monoclonal Antibody Ch14.18; Mus; Neuraxis; Neuroblastoma; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Preclinical Testing; Pump; Recurrence; Regimen; Research Personnel; Route; Safety; Schedule; Spinal Cord; Surface; Systemic Therapy; Testing; Therapeutic; Topotecan; Translating; Treatment Efficacy; Ventricular; Wireless Technology; Work; antibody-dependent cell cytotoxicity; base; cancer cell; chemotherapy; comparative efficacy; high risk; in vivo; innovation; malignant breast neoplasm; medulloblastoma; medulloblastoma cell line; melanoma; miniaturize; monoclonal antibody 3F8; mouse model; novel; novel strategies; outcome forecast; pre-clinical; research study; safety testing; scale up; sialogangliosides

DESCRIPTION (provided by applicant): Medulloblastomas (MBs) are the most common malignant brain cancers in children and frequently disseminate to the leptomeninges. Leptomeningeal MB carries poor prognosis and thus constitutes an unmet clinical need. Its therapy is suboptimal since drugs frequently do not effectively enter the cerebrospinal fluid (CSF) or are washed out rapidly. Thus, the leptomeninges are a sanctuary from systemic therapy. It is therefore imperative to develop novel approaches for drug delivery into the CSF to treat leptomeningeal MB. Our goal is to develop a new clinical approach to effectively treat leptomeningeal MB. We propose metronomic (multiple small frequent infusions) drug administration directly into the brain ventricles to achieve maxi- mal therapeutic efficacy. Therapy will be via a novel, wirelessly-operated, programmable, implantable, re- fillable micropump developed by Dr. Meng, which is now ready for preclinical testing in this R21. The main innovations of this pump are the combination of wireless control, programmability, and miniaturized packaging. Our pilot data show that this refillable pump can reliably deliver hourly infusions into the CSF over prolonged periods. In a small pilot experiment, topotecan given metronomically into the CSF via this pump induced complete remission in a mouse with leptomeningeal MB, whereas similar dose delivered intraperitoneally had no benefit. Thus, metronomic delivery of chemotherapy into the CSF may prove more effective and less toxic than systemic delivery. This R21 will test our pump in treatment of leptomeningeal MB in mice. Treatments such as chemotherapy, anti-GD2-mediated immunotherapy and others may benefit from metronomic intra-ventricular delivery via our novel wireless programmable implantable refillable pump. We hypothesize that metronomic therapy delivered directly into the CSF by our pump will be more effective against leptomeningeal MB in mice compared to the same agents delivered via other schedules/routes. We will test this using our pump in two Specific Aims: 1) To test pre-clinical safety and efficacy of metronomic intra-ventricular chemotherapy via our micro-pump in mice carrying leptomeningeal MB compared to drug delivery via other routes and schedules; 2) To test safety and efficacy of intra-ventricular anti-GD2-based immunotherapy via our micro-pump in mice carrying leptomeningeal MB compared to anti-GD2 delivery by other routes and schedules. Results from this R21 will establish principles for dosing regimen(s) for phase I clinical trials using a scaled-up version of this pump and provide the pre-clinical data fo this novel clinical approach. This work is of high significance as our novel pump will allow effective drug delivery into the leptomeninges. The clinical impact of this approach is wide, since it may also apply to other diseases or other cancers affecting the brain and spinal cord for which sustained delivery of drugs is a challenge. Thus, our application is highly novel and has high significance and potential for strong impact in an area where there is a great unmet need.

描述(申请人提供)：髓母细胞瘤(MBS)是儿童最常见的恶性脑癌，常扩散至软脑膜。软脑膜MB的预后很差，因此构成了一个未得到满足的临床需求。它的治疗方法并不理想，因为药物往往不能有效地进入脑脊液(CSF)，或者很快就会被冲走。因此，软脑膜是全身治疗的避难所。因此，开发新的药物进入脑脊液的方法来治疗软脑膜MB是当务之急。我们的目标是开发一种新的临床方法来有效地治疗软脑膜MB。我们建议节律(多次小而频繁的输注)药物直接进入脑室以达到最大的治疗效果。治疗将通过孟博士开发的一种新型、无线操作、可编程、可植入、可再填充的微泵进行，该微泵现已准备好在R21上进行临床前测试。该泵的主要创新是结合了无线控制、可编程性和小型化包装。我们的试验数据表明，这种可再充泵可以在较长时间内可靠地每小时向脑脊液输送输液。在一项小型的先导性实验中，通过这种泵将拓扑替康按节律性地注入脑脊液可诱导软脑膜MB小鼠的完全缓解，而类似剂量的腹膜内给药则没有任何好处。因此，节律性的脑脊液化疗可能比全身化疗更有效，毒性更小。这台R21将测试我们的泵在治疗小鼠软脑膜MB方面的作用。化疗、抗GD2介导的免疫治疗和其他治疗可能受益于通过我们新型无线可编程植入式可再充泵进行的节律性脑室内给药。我们推测，与通过其他计划/途径提供的相同药物相比，通过我们的泵直接进入脑脊液的节律疗法将更有效地对抗小鼠的软脑膜MB。我们将使用我们的泵进行两个特定目标的测试：1)测试通过我们的微泵对携带软脑膜MB的小鼠进行节律性脑室内化疗的临床前安全性和有效性，并与通过其他途径和时间表给药的小鼠进行比较；2)测试通过我们的微泵对携带软脑膜MB的小鼠进行脑室内抗GD2免疫治疗的安全性和有效性，并与通过其他途径和时间表给药的抗GD2进行比较。R21的结果将为使用这种泵的放大版本的I期临床试验建立剂量方案(S)的原则，并为这一新的临床方法提供临床前数据。这项工作具有很高的意义，因为我们的新型泵将允许有效的药物输送到软脑膜。这种方法的临床影响是广泛的，因为 它也可能适用于影响大脑和脊髓的其他疾病或其他癌症，对这些疾病或癌症来说，持续给药是一个挑战。因此，我们的应用具有很高的新颖性，在一个有巨大未得到满足的需求的领域具有很高的意义和强大的影响力。