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

项目总结 抗CD19嵌合抗原受体(CAR)自体T细胞 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 显示客观应答率为83%，中位数OS尚未达到2。主要 迄今为止观察到的CAR T细胞的急性毒性是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，包括困惑、迟钝、癫痫、幻觉、失语症、共济失调和 很少见，脑水肿5。现实世界中使用阿昔卡班的数据证实了强劲的应答率和 持久性，但进一步强调需要改进毒性管理，CRS和NTX比率为96% 76%，其中≥3级事件分别占17%和38%。CAR T的未来成功与应用 细胞对更广泛的患者群体的影响受到这些毒性的发生率和严重性的限制。 Anakinra是一种人类白细胞介素1受体(IL-1R)拮抗剂，已证明对 类风湿和脓毒症相关巨噬细胞激活综合征的治疗以及最近的小鼠模型 CRS和NTX9-11。这些数据提示，IL-1R的阻断可能在高血压的病理生理过程中起重要作用。 CRS和NTX，但似乎不是CAR-T细胞疗效所必需的。此外，通过 IL-1R促进IL-6的产生，因此阻断IL-1R有可能阻断IL-6的产生和 其下游后果。我们正在开设一项第二阶段的单中心开放标签研究，评估其安全性 阿纳金拉联合阿昔卡替尼治疗复发或难治性非霍奇金淋巴瘤的疗效。 我们的假设是，阻断IL-1R信号将阻止2级或更高的NTX和CRS的发展， 这将在临床上和细胞因子和免疫细胞调节的相关证据中得到明显的证明。 外周血液和脑脊液(CSF)的相互作用。Maus博士(PI)将担任IND，Dr。 Frigault(co-I)将是临床研究人员，Kite Pharma将提供药物(Axi-cel和Anakinra)作为 以及对临床研究的部分财政支持。我们寻求NIH的资金(这份R01提案)作为工资支持 供临床研究人员使用，并进行相关研究，包括提取临床数据 在CRS和NTX上使用两种不同的分级系统，进行细胞因子水平的实验室测量， 以及T细胞和髓系细胞在蛋白质上的详细表型和功能图谱 以及血液和脑脊液中的单细胞转录组水平，这将使探索机制成为可能 在存在或不存在Ankinra的情况下的免疫相互作用。我们将使用来自接受治疗的患者的样本 商业化的轴卡宾毛果作为参照物。这项研究的完成具有重要意义，因为它可能 使常规门诊使用CAR T细胞疗法，我们将使用创新的方法来定义 免疫细胞相互作用的机制和网络，驱动CRS和神经毒性。

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.