Therapy for leptomeningeal medulloblastoma by a novel implantable pump

描述（申请人提供）：髓母细胞瘤（MBs）是儿童最常见的恶性脑癌，常扩散到脑膜。轻脑膜MB预后不良，因此构成未满足的临床需求。由于药物经常不能有效地进入脑脊液（CSF）或被迅速排出，其治疗方法不是最佳的。因此，轻脑膜是全身治疗的避难所。因此，迫切需要开发一种新的方法来将药物输送到脑脊液中以治疗小脑脊膜MB。我们的目标是开发一种新的临床方法来有效治疗小脑脊膜MB。我们建议将药物直接注入脑室以达到最大的治疗效果。治疗将通过一种新颖的、无线操作的、可编程的、可植入的、可重新填充的微泵进行，该微泵由孟博士开发，现已准备好在R21进行临床前测试。该泵的主要创新是无线控制、可编程性和小型化包装的结合。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脑脊液中注入一次。在一项小型试点实验中，拓扑替康通过该泵节律性地注入脑脊液，可诱导患有小脑脊膜MB的小鼠完全缓解，而类似剂量的腹腔注射则没有任何益处。因此，节律性给药到脑脊液可能比全身给药更有效，毒性更小。这台R21将测试我们的泵对小鼠脑脊膜MB的治疗效果。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颖的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/途径给药的相同药物相比，通过我们的泵直接给药到脑脊液中的节律疗法对小鼠小脑膜MB更有效。我们将在两个特定目标中使用我们的泵进行测试：1)与通过其他途径和时间表给药相比，通过我们的微泵在携带小脑膜MB的小鼠中测试节拍器心室化疗的临床前安全性和有效性；2)与其他途径和时间表的抗gd2递送相比，通过我们的微泵在携带小脑膜MB的小鼠中进行心室内抗gd2免疫治疗的安全性和有效性。该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，并为这种新型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的药物输送到脑膜。这种方法的临床影响是广泛的，因为

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.