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: 10208809
• 负责人: Jennifer A. Wargo
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208809
• 关键词: Address; Antibodies; Blood; Breast Lymphoma; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Clinical Trials; Complication; Cytology; Diagnosis; Diagnostic radiologic examination; 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; Prognosis; 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; patient population; pembrolizumab; programmed cell death protein 1; prospective; 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：项目摘要/摘要 抑制T细胞表面PD-1的抗体已经彻底改变了T细胞的治疗和结果 转移性黑色素瘤患者。然而，转移到中枢神经系统(CNS)仍然是一种 晚期黑色素瘤的常见和破坏性并发症，而中枢神经系统是经常治疗的部位 目前的治疗方法都失败了。黑色素瘤患者有多种治疗选择 脑转移瘤。相比之下，对于发生软脑膜的患者来说，治疗的选择很少。 疾病(LMD)。LMD可以导致显著的神经功能障碍，黑色素瘤的中位存活率 LMD患者发病时间小于2个月。因此，存在着开发更有效的关键的未得到满足的需求 黑色素瘤LMD患者的治疗。曲妥珠单抗和利妥昔单抗在 乳腺癌和淋巴瘤分别表明，鞘内(IT)给药癌症 治疗可以提高LMD患者脑脊液(CSF)中的药物水平和临床益处。 我们对鞘内IL2(IT IL2)的独特和长期经验类似地证明了鞘内 免疫疗法可以在部分患有LMD的黑色素瘤患者中实现持久的疾病控制和生存。 然而，使用IT IL2的长期生存是罕见的，而IT IL2的治疗相关毒性是普遍的。因此， 对于更活跃、毒性更低的LMD治疗方法的需求仍然没有得到满足。我们假设 IT注射抗PD-1抗体是安全的，并在脑脊液中诱导抗肿瘤免疫反应 伴有LMD的转移性黑色素瘤患者。为了验证这一假设，在目标1中，我们将进行一部小说 确定IT和静脉联合用药的安全性和最大耐受量的I/Ib期研究(IV) 抗PD-1抗体nivolumab在转移性黑色素瘤LMD患者中的应用。这是审判， 最近获得FDA批准的，将是第一个评估IT抗PD-1安全性的药物，它 为LMD患者提供了一种重要的新选择。在目标2中，脑脊液和血液采集自 多个时间点的试验将被分析免疫细胞亚群和细胞因子。结果将是 分析以表征IT+IV尼伏卢单抗治疗的效果，并提高我们对 脑脊液免疫微环境。在目标3中，分离的脑脊液和血液中的无细胞肿瘤DNA(CtDNA)将 进行下一代测序(NGS)以检测和量化体细胞突变。结果将用于 评估突变负担和分布随时间的变化，并将在脑脊液中检测到的突变与 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的未得到满足的临床需求 对于患有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。