CTRIP: Treatment of Sickle Cell Crisis with inhibitors of NKT cell activation

CTRIP：用 NKT 细胞活化抑制剂治疗镰状细胞危机

• 批准号: 7940964
• 负责人: Joel M. Linden
• 金额: $ 94.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940964
• 关键词: Adenosine; Adenosine A2A Receptor; Adhesions; Adolescent; Adult; Affect; African American; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Presentation; Antigens; Biological Markers; Birth; Blood; Blood Vessels; CD1 Antigens; Cause of Death; Cell Line; Cell physiology; Cells; Childhood; Clinic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Clinical Trials Design; Data; Deferoxamine; Dependence; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Engineering; Enrollment; Ensure; Epithelial Cells; Equilibrium; Fc Receptor; Future; Genetic; Glycolipids; Goals; Hematological Disease; Hospitals; Human; Hypersensitivity; Immunology; Individual; Infarction; Inflammation; Inflammatory; Infusion procedures; Injury; Institutes; Institution; Interleukin-2; Interleukin-4; Investigation; Iron Chelation; Ischemia; Lead; Leukocytes; Lipids; Liver; Longevity; Lung Inflammation; Lymphocyte; Maximum Tolerated Dose; Messenger RNA; Morbidity - disease rate; Mus; Organ; Organ failure; Pain; Patients; Phase II Clinical Trials; Platelet Activation; Play; Population; Process; Purinergic P1 Receptors; Receptor Activation; Receptor Cell; Receptor Signaling; Recurrence; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Infrastructure; Research Personnel; Role; Safety; Scientist; Severities; Sickle Cell; Sickle Cell Anemia; Staging; Stress; Stroke; T-Cell Receptor; Techniques; Testing; Therapeutic; Tilia; Time; Tissues; United States; Washington; acute chest syndrome; arm; authority; base; cell type; drug candidate; efficacy testing; experience; fundamental research; hydroxyurea; inhibitor/antagonist; leukocyte activation; mortality; neutrophil; novel; preclinical study; public health relevance; receptor; research clinical testing; safety study; sickle cell crisis; subcutaneous; vascular inflammation

DESCRIPTION (provided by applicant): This stage one TRIP application will enable a phase II clinical trial of a new therapy to treat sickle cell disease (SCD) in two years. The basis of our proposal is our recent discovery that invariant NKT (iNKT) cells contribute importantly to tissue inflammation and injury in SCD mice. These cells are increased in number and activated in the blood of patients with SCD. Adenosine A2A receptors (A2AR) are highly expressed on iNKT cells and A2A agonists inhibit iNKT cell activation and reduce tissue damage in SCD mice. We hypothesize that A2A agonists will reduce inflammatory biomarkers in patient blood and reduce the duration and severity of painful SCD crises. We will use the A2A agonist, Lexiscan, that is clinically approved as a pharmacological stress agent, to conduct pilot safety and biomarker studies. In addition we will evaluate in mice additional anti-iNKT cell drug candidates that can be tested as alternatives to Lexiscan in subsequent clinical studies. We have assembled an expert team of clinical and basic investigators from three institutions. These include the Co-PI, David Nathan, M.D., a thought leader in SCD treatment who originated hydroxyurea therapy; and four other clinician scientists who direct adult and juvenile SCD clinics that will provide patients for these studies at Washington U., or Harvard-affiliated hospitals: Drs Joshua Field, Michael DeBaun, Maureen Okam and Mathew Heeney. The analysis of human blood for biomarkers will be conducted at the La Jolla Institute of Allergy and Immunology (LIAI) using cutting-edge flow cytometric techniques and overseen by the Basic Co-PI, Joel Linden, PhD, who discovered that iNKT cells exacerbate tissue injury in SCD mice and that iNKT cells are inhibited by A2A agonists. Co-investigators who will help evaluate iNKT cell function are two of the world's leading authorities on NKT cells, Drs. Mitch Kronenberg of LIAI and Mark Exley or Harvard. The aims for this stage I TRIP are summarized as follows: Preclinical studies: Aim 1 is to determine the optimal dose and duration of Lexiscan needed to reduce liver and lung inflammation and injury and reduce leukocyte activation in NY1DD (SCD) mice; Aim 2 is to evaluate anti-iNKTCR antibodies and novel glycolipid antagonists of iNKT receptors to determine if they are therapeutic candidates that can reduce tissue injury in SCD mice. Preliminary SCD clinical studies: Aim 3 is to conduct a small dose escalation study with Lexiscan infused for 12 h to determine the maximal tolerated dose (MTA) in SCD patients; Aim 4 is to evaluate the MTD for safety during infusion for 24 h; Aim 5 is to evaluate the MTD for safety in adult and juvenile patients during painful crises. During these studies we also will examine biomarkers of inflammation in the blood of patients. The primary goal of this stage one TRIP proposal is to prepare for a phase 2 clinical trial of Lexiscan for sickle cell painful crisis. Secondary goals are to prepare for a clinical trial of Lexiscan for acute chest syndrome, and to ready anti-iNKT cell receptor antibodies and glypolipid antagonists for future clinical evaluation in SCD. PUBLIC HEALTH RELEVANCE: Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, affecting about 80,000 people (1 of every 600 African Americans). It causes short life span, pain and multi-organ failure. We have discovered a new anti-inflammatory approach to effectively treat SCD in mice and we plan to evaluate this new therapy in patients with SCD.

描述（由申请人提供）：这一阶段的 TRIP 申请将在两年内开展治疗镰状细胞病 (SCD) 新疗法的 II 期临床试验。我们建议的基础是我们最近发现不变的 NKT (iNKT) 细胞对 SCD 小鼠的组织炎症和损伤有重要影响。这些细胞在 SCD 患者的血液中数量增加并被激活。腺苷 A2A 受体 (A2AR) 在 iNKT 细胞上高表达，A2A 激动剂可抑制 SCD 小鼠的 iNKT 细胞激活并减少组织损伤。我们假设 A2A 激动剂将减少患者血液中的炎症生物标志物，并减少痛苦的 SCD 危象的持续时间和严重程度。我们将使用经临床批准作为药理应激剂的 A2A 激动剂 Lexiscan 来进行试点安全性和生物标志物研究。此外，我们将在小鼠中评估其他抗 iNKT 细胞候选药物，这些候选药物可以在后续临床研究中作为 Lexiscan 的替代品进行测试。 我们组建了一支由来自三个机构的临床和基础研究人员组成的专家团队。其中包括 Co-PI David Nathan 医学博士，他是 SCD 治疗领域的思想领袖，是羟基脲疗法的创始人；以及其他四位临床科学家，他们指导成人和青少年 SCD 诊所，为华盛顿大学或哈佛附属医院的这些研究提供患者：Joshua Field 博士、Michael DeBaun 博士、Maureen Okam 博士和 Mathew Heeney 博士。拉霍亚过敏和免疫学研究所 (LIAI) 将使用尖端流式细胞术技术对人类血液进行生物标志物分析，并由基本联合 PI Joel Linden 博士监督，他发现 iNKT 细胞会加剧组织SCD 小鼠的损伤以及 iNKT 细胞被 A2A 激动剂抑制。帮助评估 iNKT 细胞功能的共同研究人员是两位世界领先的 NKT 细胞权威，Drs. LIAI 的 Mitch Kronenberg 和哈佛大学的 Mark Exley。第一阶段 TRIP 的目标概括如下： 临床前研究：目标 1 是确定 NY1DD (SCD) 小鼠中减少肝脏和肺部炎症和损伤以及减少白细胞活化所需的 Lexiscan 的最佳剂量和持续时间；目标 2 是评估抗 iNKTCR 抗体和新型 iNKT 受体糖脂拮抗剂，以确定它们是否是可以减少 SCD 小鼠组织损伤的候选治疗药物。 初步SCD临床研究：目标3是进行Lexiscan输注12小时的小剂量递增研究，以确定SCD患者的最大耐受剂量（MTA）；目标4是评估24小时输注期间的安全性MTD；目标 5 是评估成人和青少年患者在痛苦危机期间的 MTD 安全性。在这些研究中，我们还将检查患者血液中炎症的生物标志物。 TRIP 第一阶段提案的主要目标是为 Lexiscan 治疗镰状细胞疼痛危机的第二阶段临床试验做准备。次要目标是为 Lexiscan 治疗急性胸部综合征的临床试验做准备，并为未来 SCD 的临床评估准备好抗 iNKT 细胞受体抗体和糖脂拮抗剂。 公共卫生相关性：镰状细胞病 (SCD) 是美国最常见的遗传性血液疾病，影响约 80,000 人（每 600 名非裔美国人中就有 1 人）。它会导致寿命短、疼痛和多器官衰竭。我们发现了一种新的抗炎方法可以有效治疗小鼠的 SCD，我们计划在 SCD 患者中评估这种新疗法。