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（由申请人提供）：髓母细胞瘤（MB）是儿童中最常见的恶性脑癌，并且经常扩散至软脑膜。软脑膜 MB 预后较差，因此构成了未满足的临床需求。由于药物经常不能有效地进入脑脊液 (CSF) 或被迅速冲走，因此其治疗效果不佳。因此，软脑膜是全身治疗的避难所。因此，必须开发新的方法将药物输送到脑脊液中来治疗软脑膜 MB。我们的目标是开发一种新的临床方法来有效治疗软脑膜 MB。我们建议将药物直接注射到脑室中，以达到最大的治疗效果。治疗将通过孟博士开发的新型、无线操作、可编程、可植入、可再填充的微型泵进行，该泵现已准备好在 R21 中进行临床前测试。该泵的主要创新点是无线控制、可编程性和小型化封装的结合。我们的试验数据表明，这种可再填充泵可以在较长时间内可靠地每小时向脑脊液中输注。在一项小型试点实验中，拓扑替康通过该泵有节奏地注入脑脊液，使患有软脑膜 MB 的小鼠得到完全缓解，而腹膜内输送的类似剂量则没有任何益处。因此，节律地将化疗药物输送到脑脊液可能比全身输送更有效且毒性更小。该 R21 将测试我们的泵对小鼠软脑膜 MB 的治疗效果。化疗、抗 GD2 介导的免疫疗法等治疗可能受益于通过我们新型无线可编程植入式可再填充泵进行的节律性心室内输送。我们假设，与通过其他时间表/途径递送的相同药物相比，通过我们的泵直接递送至脑脊液的节拍疗法对小鼠的软脑膜MB更有效。我们将使用我们的泵在两个具体目标中对此进行测试：1) 与通过其他途径和时间表的药物输送相比，测试通过我们的微型泵在携带软脑膜 MB 的小鼠中进行节拍性心室内化疗的临床前安全性和有效性； 2) 与通过其他途径和时间表进行抗 GD2 递送相比，测试通过我们的微泵对携带软脑膜 MB 的小鼠进行基于抗 GD2 的心室内免疫治疗的安全性和有效性。 R21 的结果将为使用该泵的放大版本的 I 期临床试验建立给药方案原则，并为这种新颖的临床方法提供临床前数据。这项工作具有重要意义，因为我们的新型泵将允许有效地将药物输送到软脑膜中。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，对于这些疾病或癌症，持续输送药物是一个挑战。因此，我们的应用程序非常新颖，并且在需求未得到满足的领域具有很高的意义和产生强烈影响的潜力。