Efficacy and immune effects of anakinra prophylaxis for neurologic toxicity and cytokine release syndrome in patients with lymphoma receiving axicabtagene ciloleucel

阿那白滞素预防对接受 axicabtagene ciloleucel 的淋巴瘤患者的神经毒性和细胞因子释放综合征的疗效和免疫作用

• 批准号: 10034347
• 负责人: Marcela Valderrama Maus
• 金额: $ 69.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10034347
• 关键词: Adult; Aphasia; Ataxia; Autologous; B-Cell Lymphomas; Blood; Brain; CAR T cell therapy; CD19 Antigens; CD19 gene; CD28 gene; CD3 Antigens; Cell Communication; Cell Compartmentation; Cells; Cerebral Edema; Cerebrospinal Fluid; Cerebrum; Childhood Leukemia; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Confusion; Correlative Study; Data; Development; Endothelium; Engineering; Event; FDA approved; Fc Receptor; Fever Chills; Financial Support; Functional disorder; Funding; Future; Genetic Transcription; Hallucinations; Human; Hypotension; Hypoxia; Immune; In complete remission; Incidence; Infusion procedures; Inpatients; Interleukin 6 Receptor; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Laboratories; Large-Cell Lymphomas; Link; Lymphoma; Macrophage activation syndrome; Maps; Measurement; Measures; Mediating; Methods; Myeloid Cells; Neurologic; Neurologic Symptoms; Neurological outcome; Non-Hodgkin' s Lymphoma; Outpatients; Participant; Pathogenicity; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Play; Production; Prophylactic treatment; Proteins; Receptor Signaling; Refractory; Relapse; Research Personnel; Role; Safety; Sampling; Seizures; Sepsis; Severities; Signal Transduction; Specificity; Steroids; Stupor; Symptoms; System; T-Lymphocyte; Therapeutic Agents; Toxic effect; United States National Institutes of Health; Wages; Work; abstracting; acute toxicity; anakinra; antitumor effect; base; chimeric antigen receptor; chimeric antigen receptor T cells; clinical efficacy; cytokine; cytokine release syndrome; experience; extracellular; improved; innovation; leukemia/lymphoma; monocyte; mouse model; neurotoxicity; objective response rate; open label; patient population; peripheral blood; prevent; prophylactic; receptor; response; side effect; single-cell RNA sequencing; success; transcriptome

PROJECT SUMMARY Axicabtagene ciloleucel are autologous anti-CD19 chimeric antigen receptor (CAR) T cells that have been FDA approved for treatment of relapsed or refractory large cell lymphoma. The ZUMA-1 registration study demonstrated an objective response rate of 83% with a median OS that has not been reached 2. The primary acute toxicities observed to date with CAR T cells have been cytokine release synderom (CRS) and neurotoxicity (NTX). CRS is defined as a constellation of symptoms which may include fever, chills, hypotension, and hypoxia. Manifestations of NTX vary and include confusion, obtundation, seizures, hallucinations, aphasia, ataxia, and rarely, cerebral edema5. Real world data with axicabtagene has confirmed the robust response rates and durability, but further emphasized the need for improved toxicity management, with CRS and NTX rates of 96% and 76%, with grade ≥ 3 events in 17% and 38%, respectively4. The future success and application of CAR T cells to a broader population of patients is limited by the incidence and severity of these toxicities. Anakinra, a human interleukin 1 receptor (IL-1R) antagonist, has demonstrated clinical efficacy in the treatment of rheumatoid and sepsis related macrophage activation syndrome, as well as in recent mouse models of CRS and NTX9-11. These data suggest that IL-1R blockade may play a critical role in the pathophysiology of both CRS and NTX, but does not appear to be required for CAR-T cell efficacy. Furthermore, signaling through IL-1R potentiates IL-6 production, and blockade of IL-1R therefore has the potential to block IL-6 production and its downstream consequences. We are opening a Phase 2 single center, open-label study evaluating the safety and efficacy of anakinra when combined with axicabtagene ciloleucel in subjects with relapsed or refractory NHL. Our hypothesis is that blocking IL-1R signaling will prevent the development of grade 2 or higher NTX and CRS, and that this will be evident clinically and by correlative evidence of modulation of cytokines and immune cell interactions in the peripheral blood and cerebrospinal fluid (CSF). Dr. Maus (PI) will be holding the IND, Dr. Frigault (co-I) will be the clinical investigator, and Kite Pharma will provide the drugs (axi-cel and anakinra) as well as partial financial support for the clinical study. We seek NIH funding (this R01 proposal) for salary support for the investigators of the clinical study and to conduct the correlative studies, including abstracting clinical data on CRS and NTX using two different grading systems, conducting laboratory measurements of cytokine levels, and detailed phenotyping and functional mapping of both the T cell and myeloid cell compartments at the protein and single-cell transcriptome level in the blood and cerebral spinal fluid that will enable probing the mechanisms of immune interactions in the presence or absence of ankinra. We will use samples from patients treated with commercial axicabtagene ciloleucel as comparators. Completion of this study is significant because it could enable routine outpatient use of CAR T cell therapy, and we will use innovative methods to define the mechanisms and networks of immune cell interactions that drive CRS and neurotoxicity.

项目摘要 axabtagene cileoleucel是自体抗CD19嵌合抗原受体（CAR）T细胞 我们获得了FDA的批准用于治疗中继或难治性大细胞淋巴瘤。 Zuma-1注册研究 证明尚未达到的中位OS的客观响应率为83％2。 迄今为止使用CAR T细胞观察到的急性毒性是细胞因子释放综合症（CRS）和神经毒性 （NTX）。 CRS定义为症状的星座，可能包括发烧，发冷，低血压和缺氧。 NTX的表现各不相同，包括混乱，客观，癫痫发作，幻觉，失语症，共济失调和 很少，脑湿肿5。使用Axibabtagene的现实世界数据已经确认了稳健的响应率和 耐用性，但进一步强调需要提高毒性管理，CRS和NTX率为96％ 和76％，分别为17％和38％的3级事件。汽车的未来成功和应用 这些毒性的事件和严重程度的限制，对广泛的患者群体的细胞受到限制。 人白细胞介素1受体（IL-1R）拮抗剂Anakinra在 类风湿和败血症相关的巨噬细胞激活综合征的处理，以及最近的小鼠模型 CRS和NTX9-11。这些数据表明IL-1R桶在 CRS和NTX都不是CAR-T细胞效率所必需的。此外，发出信号 IL-1R电位IL-6产生和IL-1R的阻断具有阻断IL-6产生的潜力和 它的下游后果。我们正在开设一个2阶段单中心，开放标签研究，以评估安全性 并在具有继电器或难治性NHL受试者中与Axicabtagene Cileleucel结合使用Anakinra。 我们的假设是阻止IL-1R信号传导将防止2级或更高级别的NTX和CRS的发展， 这将是临床上的证据，并通过调节细胞因子和免疫核管的相关证据 外周血和脑脊液（CSF）中的相互作用。 Maus博士（PI）将持有Ind，博士 Frigault（Co-I）将是临床研究者，风筝制药将提供药物（Axi-Cel和Anakinra）作为 作为临床研究的部分财政支持。我们寻求NIH资金（此R01提案）寻求工资支持 对于临床研究的研究者并进行相关研究，包括抽象临床数据 在CRS和NTX上使用两个不同的分级系统，进行细胞因子水平的实验室测量， 以及T细胞和髓样细胞室的详细表型和功能映射在蛋白质上 血液和脑脊髓液中的单细胞转录组水平，这些水平将探测机制 在存在或不存在Ankinra的情况下免疫相互作用的。我们将使用接受治疗的患者的样本 商业axipabtagene cileoleucel作为比较器。这项研究的完成很重要，因为它可以 启用常规门诊CAR T细胞疗法，我们将使用创新方法来定义 驱动CRS和神经毒性的免疫相互作用的机理和网络。