Therapy for leptomeningeal medulloblastoma by a novel implantable pump

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，经常扩散到软脑膜。软脑膜MB预后差，因此构成未满足的临床需求。它的治疗是次优的，因为药物经常不能有效地进入脑脊液（CSF）或被迅速冲洗掉。因此，软脑膜是全身治疗的避难所。因此，迫切需要开发用于将药物递送到CSF中以治疗软脑膜MB的新方法。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。我们建议节拍式（多次小频率输注）药物直接注入脑室，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、可重新填充的微型泵进行，该微型泵现已准备在R21中进行临床前测试。该泵的主要创新是无线控制、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长时间内可靠地每小时向CSF输注一次。在一项小型中试实验中，通过该泵将拓扑替康节律性地给予CSF中，诱导软脑膜MB小鼠完全缓解，而腹腔内给予相似剂量则无获益。因此，将化疗节律性地递送到CSF中可能证明比全身递送更有效且毒性更小。该R21将测试我们的泵在小鼠软脑膜MB治疗中的作用。化疗、抗GD2介导的免疫治疗等治疗可能会受益于通过我们的新型无线可编程植入式可再填充泵进行的节拍式心室内输送。我们假设，与通过其他方案/途径递送的相同药物相比，通过我们的泵直接递送到CSF中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特定目的中对此进行测试：1）测试与通过其他途径和时间表的药物递送相比，通过我们的微泵在携带软脑膜MB的小鼠中进行节拍式心室内化疗的临床前安全性和有效性; 2）为了测试与抗GD2相比，通过我们的微泵在携带软脑膜MB的小鼠中进行基于抗GD2的脑室内免疫治疗的安全性和有效性，GD2通过其他路线和时间表交付。本R21的结果将为使用该泵的放大版本的I期临床试验确立给药方案的原则，并为这种新型临床方法提供临床前数据。这项工作是非常重要的，因为我们的新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 它也可应用于影响脑和脊髓的其他疾病或其他癌症，对于这些疾病或癌症，持续递送药物是一个挑战。因此，我们的应用是非常新颖的，具有很高的意义和潜力，在一个有很大的未满足的需求的领域产生强烈的影响。

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.