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的抗体已彻底改变了治疗和结果 转移性黑色素瘤患者。但是，中枢神经系统（CNS）转移仍然是 晚期黑色素瘤和CNS的常见和破坏性并发症是经常治疗部位 当前疗法的失败。黑色素瘤患者有多种治疗选择 脑转移。相比之下，患有瘦脑的患者几乎没有治疗选择 疾病（LMD）。 LMD会引起明显的神经缺陷，而黑色素瘤的中位生存期 LMD患者少于2个月。因此，有一个至关重要的未满足需要发展更有效的 来自黑色素瘤LMD患者的治疗。以前关于曲妥珠单抗和利妥昔单抗的经验 乳腺癌和淋巴瘤分别证明了癌症的给药 疗法可以提高脑脊液（CSF）的药物水平和LMD患者的临床益处。 我们在鞘内IL2（IT IL2）上的独特和长期经验类似地表明了鞘内 免疫疗法可以在LMD的黑色素瘤患者的一部分中获得持久的疾病控制和存活。 但是，IL2的长期生存很少见，与治疗相关的毒性IL2是普遍的。因此， 对LMD的疗法仍未满足，该疗法更活跃，毒性较小。我们假设这一点 IT抗PD-1抗体的给药将是安全的，并在CSF中诱导抗肿瘤免疫反应 LMD转移性黑色素瘤患者。为了检验这一假设，在AIM 1中，我们将进行新颖 I/IB期研究以确定合并和静脉内（IV）的安全性和最大耐受剂量（IV） LMD转移性黑色素瘤患者的抗PD-1抗体nivolumab的给药。这是审判， 最近已获得FDA批准的，将是第一个评估IT抗PD-1的安全性的人，IT 对于LMD患者来说，这是一个重要的新选择。在AIM 2中，从患者中收集的CSF和血液 将分析多个时间点的试验中的免疫细胞子集和细胞因子。结果将是 分析以表征IT + iv nivolumab治疗的影响，并提高我们对 CSF的免疫微环境。在AIM 3中，无细胞的肿瘤DNA（CTDNA）分离的CSF和血液将 接受下一代测序（NGS）以检测和量化体细胞突变。结果将用于 随着时间的推移，评估突变负担和轮廓的变化，并比较CSF中检测到的突变 在血液和肿瘤组织中检测到的人。这些研究共同解决了对新的临床需求 黑色素瘤患者患有LMD的治疗选择，并提高我们对分子和分子的理解 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 信息以对黑色素瘤和其他癌症类型的LMD患者进行优先级和优化未来的试验。