Project 2 Intrathecal Anti-PD-1 Immunotherapy for Metastatic Melanoma Patients with Leptomeningeal Disease (LMD)

项目2：项目概要/摘要 抑制T细胞表面上的PD-1的抗体已经彻底改变了帕金森病的治疗和结果。 转移性黑素瘤患者。然而，转移到中枢神经系统（CNS）仍然是一个严重的问题。 晚期黑色素瘤的常见和毁灭性并发症，CNS是治疗的常见部位 目前的治疗失败。有多种治疗选择的黑色素瘤患者的实质 脑转移相比之下，对于出现软脑膜炎的患者， 疾病（LMD）。LMD可导致严重的神经功能缺损， LMD患者的发病时间小于2个月。因此，开发更有效的 治疗黑色素瘤导致的LMD患者。既往使用曲妥珠单抗和利妥昔单抗治疗 乳腺癌和淋巴瘤分别已经证明， 治疗可以增加脑脊液（CSF）中的药物水平和LMD患者的临床益处。 我们对鞘内IL-2（IT IL-2）的独特和长期经验同样表明， 免疫疗法可以在患有LMD的黑色素瘤患者的子集中实现持久的疾病控制和存活。 然而，使用IT IL 2的长期存活是罕见的，并且使用IT IL 2的治疗相关毒性是普遍的。因此，在本发明中， 对于更有活性和毒性更小的LMD疗法仍然存在未满足的需求。我们假设 IT给予抗PD-1抗体将是安全的，并在CSF中诱导抗肿瘤免疫应答。 患有LMD的转移性黑素瘤患者。为了验证这一假设，在目标1中，我们将进行一项新的 确定IT和静脉（IV）联合给药的安全性和最大耐受剂量的I/Ib期研究 在患有LMD的转移性黑素瘤患者中施用抗PD-1抗体纳武单抗。这是审判 最近已被FDA批准，将是第一个评估IT抗PD-1的安全性，它 是LMD患者的一种重要的新选择。在目标2中，从患者中收集的CSF和血液 将分析多个时间点的试验的免疫细胞亚群和细胞因子。结果将 分析以表征IT + IV纳武利尤单抗治疗的效果，并提高我们对 CSF的免疫微环境在目标3中，分离的CSF和血液中的无细胞肿瘤DNA（ctDNA）将被用于检测肿瘤细胞。 进行下一代测序（NGS）以检测和量化体细胞突变。结果将用于 评估突变负荷和谱随时间的变化，并将CSF中检测到的突变与 在血液和肿瘤组织中检测到的。这些研究共同解决了新的未满足的临床需求， LMD黑色素瘤患者的治疗选择，并提高我们对LMD的分子和 这种侵略性疾病的免疫特征。这些研究的结果也将提供重要的 这些信息可以优先考虑和优化未来针对黑色素瘤和其他癌症类型LMD患者的试验。

Project 2: Project Summary/ Abstract Antibodies that inhibit PD-1 on the surface of T cells have revolutionized the treatment and outcomes of patients with metastatic melanoma. However, metastasis to the central nervous system (CNS) remains a common and devastating complication of advanced melanoma, and the CNS is a frequent site of treatment failure for current therapies. There are multiple treatment options for melanoma patients with parenchymal brain metastases. In contrast, there are very few treatment options for patients that develop leptomeningeal disease (LMD). LMD can cause significant neurological deficits, and the median survival for melanoma patients with LMD is less than 2 months. Thus, there is a critical unmet need to develop more effective treatments for patients with LMD from melanoma. Previous experience with trastuzumab and rituximab in breast cancer and lymphoma, respectively, have demonstrated that intrathecal (IT) administration of cancer therapies can increase drug levels in the cerebrospinal fluid (CSF) and clinical benefit in patients with LMD. Our unique and long-term experience with intrathecal IL2 (IT IL2) has similarly demonstrated that intrathecal immunotherapy can achieve durable disease control and survival in a subset of melanoma patients with LMD. However, long-term survival with IT IL2 is rare, and treatment-related toxicity with IT IL2 is universal. Thus, there remains an unmet need for therapies for LMD that are more active and less toxic. We hypothesize that IT administration of anti-PD-1 antibodies will be safe and induce an anti-tumor immune response in the CSF in metastatic melanoma patients with LMD. In order to test this hypothesis, in Aim 1 we will conduct a novel phase I/Ib study to determine the safety and maximum tolerated dose of combined IT and intravenous (IV) administration of the anti-PD-1 antibody nivolumab in metastatic melanoma patients with LMD. This is trial, which has recently been approved by the FDA, will be the first to assess the safety of IT anti-PD-1, and it represents an important new option for patients with LMD. In Aim 2, CSF and blood collected from patients in the trial at multiple timepoints will be analyzed for immune cell subsets and cytokines. The results will be analyzed to characterize the effects of IT + IV nivolumab treatment, and to improve our understanding of the immune microenvironment of the CSF. In Aim 3, cell-free tumor DNA (ctDNA) isolated CSF and blood will undergo next generation sequencing (NGS) to detect and quantify somatic mutations. Results will be used to evaluate changes in mutation burden and profile over time, and to compare mutations detected in the CSF to those detected in blood and in tumor tissue. Together these studies address an unmet clinical need for new treatment options for melanoma patients with LMD, and to improve our understanding of the molecular and immune features of this aggressive disease. The results of these studies will also provide important information to prioritize and optimize future trials for patients with LMD from melanoma and other cancer types.