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: 10621271
• 负责人: Marcela Valderrama Maus
• 金额: $ 68.33万
• 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/10621271
• 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; Childhood Leukemia; Chills; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Confusion; Correlative Study; Data; Development; Endothelium; Engineering; Event; FDA approved; Fc Receptor; Fever; Financial Support; Functional disorder; Funding; Future; Gene Expression Profile; 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; Proliferating; 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; 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; tocilizumab; 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.

项目概要 Axicabtagene ciloleucel 是自体抗 CD19 嵌合抗原受体 (CAR) T 细胞，具有 已被 FDA 批准用于治疗复发或难治性大细胞淋巴瘤。 ZUMA-1 注册研究 显示客观缓解率为 83%，中位 OS 尚未达到 2。 迄今为止观察到的 CAR T 细胞急性毒性包括细胞因子释放综合征 (CRS) 和神经毒性 （NTX）。 CRS 被定义为一系列症状，可能包括发烧、寒战、低血压和缺氧。 NTX 的表现多种多样，包括精神错乱、迟钝、癫痫发作、幻觉、失语、共济失调和 很少有脑水肿5。 axicabtagene 的真实世界数据证实了稳健的反应率和 耐久性，但进一步强调需要改进毒性管理，CRS 和 NTX 率为 96% 和 76%，≥ 3 级事件的比例分别为 17% 和 38%4。 CAR T未来的成功与应用 细胞向更广泛的患者群体推广受到这些毒性的发生率和严重程度的限制。 Anakinra 是一种人白细胞介素 1 受体 (IL-1R) 拮抗剂，已在 治疗类风湿和败血症相关的巨噬细胞激活综合征，以及最近的小鼠模型 CRS 和 NTX9-11。这些数据表明IL-1R阻断可能在病理生理学中发挥关键作用 CRS 和 NTX，但似乎不是 CAR-T 细胞功效所必需的。此外，通过信号传递 IL-1R 增强 IL-6 的产生，因此阻断 IL-1R 有可能阻止 IL-6 的产生 其下游后果。我们正在开展一项第二阶段单中心、开放标签研究，评估安全性 以及阿那白滞素与 axicabtagene ciloleucel 联合治疗复发性或难治性 NHL 受试者的疗效。 我们的假设是阻断 IL-1R 信号传导将阻止 2 级或更高级别的 NTX 和 CRS 的发展， 这在临床上以及通过细胞因子和免疫细胞调节的相关证据将是显而易见的 外周血和脑脊液（CSF）中的相互作用。 Maus 博士（PI）将主持 IND， Frigault (co-I) 将担任临床研究者，Kite Pharma 将提供药物（axi-cel 和 anakinra）作为 以及临床研究的部分财政支持。我们寻求 NIH 资金（本 R01 提案）来支持薪资 供临床研究的研究者进行相关研究，包括提取临床数据 使用两种不同的分级系统对 CRS 和 NTX 进行细胞因子水平的实验室测量， 以及蛋白质处 T 细胞和骨髓细胞区室的详细表型分析和功能图谱 以及血液和脑脊液中的单细胞转录组水平，这将有助于探索其机制 存在或不存在 ankinra 时的免疫相互作用。我们将使用接受过治疗的患者的样本 商业 axicabtagene ciloleucel 作为比较剂。完成这项研究意义重大，因为它可以 使 CAR T 细胞疗法能够在门诊常规使用，我们将使用创新方法来定义 驱动 CRS 和神经毒性的免疫细胞相互作用的机制和网络。