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

描述（由申请人提供）：这项一期TRIP申请将在两年内实现一种治疗镰状细胞病（SCD）的新疗法的二期临床试验。我们的建议的基础是我们最近发现不变的NKT （iNKT）细胞在SCD小鼠的组织炎症和损伤中起重要作用。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SCD小鼠的iNKT细胞上高表达，A2A激动剂抑制iNKT细胞活化，减轻组织损伤。我们假设A2A激动剂将减少患者血液中的炎症生物标志物，减少疼痛SCD危像的持续时间和严重程度。我们将使用A2A激动剂Lexiscan进行试点安全性和生物标志物研究，该药物已被临床批准为药理学应激剂。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随后的临床研究中作为Lexiscan的替代品进行测试。我们汇集了来自三个机构的临床和基础研究专家团队。其中包括联合首席研究员David Nathan，他是SCD治疗领域的思想领袖，首创了羟基脲疗法；以及另外四位指导成人和青少年SCD诊所的临床科学家，他们将在华盛顿大学或哈佛附属医院为这些研究提供患者：约书亚·菲尔德博士，迈克尔·德本，莫林·奥卡姆和马修·希尼。人类血液的生物标志物分析将在La Jolla过敏和免疫学研究所（LIAI）进行，使用尖端的流细胞技术，并由Basic Co-PI Joel Linden博士监督，他发现iNKT细胞会加剧SCD小鼠的组织损伤，并且iNKT细胞会被A2A激动剂抑制。帮助评估iNKT细胞功能的合作研究者是两位世界上NKT细胞的权威。LIAI的Mitch Kronenberg和哈佛大学的Mark Exley。临床前研究：目的1是确定Lexiscan减轻NY1DD （SCD）小鼠肝脏和肺部炎症和损伤以及降低白细胞活化所需的最佳剂量和持续时间；目的2是评估抗inktcr抗体和iNKT受体的新型糖脂拮抗剂，以确定它们是否可以减轻SCD小鼠的组织损伤。SCD初步临床研究：目的3是进行一项小剂量递增研究，用Lexiscan输注12小时，以确定SCD患者的最大耐受剂量（MTA）；目的4：评价MTD在24 h输注过程中的安全性；目的5是评估MTD在成人和青少年患者疼痛危机期间的安全性。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。这项第一阶段的TRIP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治疗急性胸综合征的临床试验做准备，并准备抗inkt细胞受体抗体和糖脂拮抗剂，用于未来SCD的临床评估。

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.