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

项目2 鞘内注射抗PD-1免疫疗法治疗患有软脑膜疾病（LMD）的转移性黑色素瘤患者

• 批准号: 10415939
• 负责人: Isabella Claudia Glitza
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415939
• 关键词: Address; Blood; Breast Lymphoma; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Clinical Trials; Complication; Cytology; Diagnosis; Disease; Evaluation; Exhibits; FDA approved; Future; Goals; IL2 gene; Immune; Immunotherapy; Incidence; Institution; Interleukin-2; Intravenous; Lymphocyte; Maximum Tolerated Dose; Medical; Metastatic Melanoma; Metastatic Neoplasm to the Central Nervous System; Metastatic Neoplasm to the Leptomeninges; Metastatic malignant neoplasm to brain; Minority; Molecular; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Neuraxis; Neurologic Deficit; Neurologic Examination; Nivolumab; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase 1/1b Clinical Trial; Resources; Safety; Sampling; Site; Somatic Mutation; Standardization; Surface; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Time; Toxic effect; Translational Research; Trastuzumab; Treatment Failure; Treatment outcome; Treatment-related toxicity; Tumor Tissue; University of Texas M D Anderson Cancer Center; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; base; cancer cell; cancer therapy; cancer type; clinical diagnosis; cytokine; design; disorder control; effective therapy; experience; first-in-human; immunoregulation; improved; inhibiting antibody; malignant breast neoplasm; melanoma; mortality; neuro-oncology; next generation sequencing; novel; novel therapeutic intervention; pembrolizumab; programmed cell death protein 1; prospective; radiological imaging; response; rituximab; targeted treatment; treatment response; treatment site; tumor DNA; tumor-immune system interactions; working group

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.

项目 2：项目总结/摘要 抑制 T 细胞表面 PD-1 的抗体彻底改变了治疗和结果 患有转移性黑色素瘤的患者。然而，向中枢神经系统（CNS）的转移仍然是一个难题。 晚期黑色素瘤常见且具有破坏性的并发症，中枢神经系统是常见的治疗部位 目前的疗法失败。对于伴有实质性病变的黑色素瘤患者有多种治疗选择 脑转移。相比之下，对于患有软脑膜炎的患者来说，治疗选择很少 疾病（LMD）。 LMD 可导致显着的神经功能缺陷以及黑色素瘤的中位生存期 LMD患者病程小于2个月。因此，迫切需要开发更有效的 黑色素瘤 LMD 患者的治疗。既往使用曲妥珠单抗和利妥昔单抗的经验 乳腺癌和淋巴瘤分别已证实鞘内 (IT) 治疗癌症 治疗可以增加 LMD 患者脑脊液 (CSF) 中的药物水平和临床获益。 我们在鞘内注射 IL2 (IT IL2) 方面独特且长期的经验也同样证明，鞘内注射 IL2 免疫疗法可以在一部分患有 LMD 的黑色素瘤患者中实现持久的疾病控制和生存。 然而，IT IL2 的长期存活很少见，而且 IT IL2 治疗相关的毒性是普遍存在的。因此， 对活性更强、毒性更小的 LMD 疗法的需求仍未得到满足。我们假设 抗 PD-1 抗体的 IT 给药将是安全的，并且会在脑脊液中诱导抗肿瘤免疫反应 患有 LMD 的转移性黑色素瘤患者。为了检验这个假设，在目标 1 中我们将进行一部小说 I/Ib 期研究以确定联合 IT 和静脉注射 (IV) 的安全性和最大耐受剂量 在患有 LMD 的转移性黑色素瘤患者中使用抗 PD-1 抗体 nivolumab。这是审判， 最近获得 FDA 批准，将是第一个评估 IT 抗 PD-1 安全性的项目， 对于 LMD 患者来说，这是一个重要的新选择。在目标 2 中，从患者身上采集脑脊液和血液 将在多个时间点对试验进行免疫细胞亚群和细胞因子分析。结果将是 分析以表征 IT + IV nivolumab 治疗的效果，并提高我们对 脑脊液的免疫微环境。在目标 3 中，分离出脑脊液和血液的无细胞肿瘤 DNA (ctDNA) 进行下一代测序（NGS）以检测和量化体细胞突变。结果将用于 评估突变负担和概况随时间的变化，并将 CSF 中检测到的突变与 在血液和肿瘤组织中检测到的那些。这些研究共同解决了新药未满足的临床需求 患有 LMD 的黑色素瘤患者的治疗选择，并提高我们对分子和 这种侵袭性疾病的免疫特征。这些研究的结果也将提供重要的 为黑色素瘤和其他癌症类型的 LMD 患者确定优先顺序和优化未来试验的信息。