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

项目摘要 Axicabtagene ciloleucel是自体抗CD 19嵌合抗原受体（CAR）T细胞， FDA已批准用于治疗复发性或难治性大细胞淋巴瘤。ZUMA-1注册研究 客观缓解率为83%，中位OS未达到2。主 迄今观察到的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定义为一系列症状，可能包括发热、寒战、低血压和缺氧。 NTX的表现各不相同，包括意识模糊、迟钝、癫痫发作、幻觉、失语症、共济失调和 罕见脑水肿5.真实的世界数据证实了阿昔卡他汀的稳健缓解率， 持久性，但进一步强调需要改善毒性管理，CRS和NTX率为96% 和76%，≥ 3级事件分别为17%和38% 4。CAR T的未来成功和应用 将细胞用于更广泛的患者群体受到这些毒性的发生率和严重程度的限制。 阿那白滞素是一种人白细胞介素1受体（IL-1 R）拮抗剂，已证实在 治疗类风湿和脓毒症相关的巨噬细胞活化综合征，以及最近的小鼠模型 CRS和NTX 9 -11。这些数据表明，IL-1 R阻断可能在脑梗死的病理生理学中起关键作用。 CRS和NTX，但似乎不是CAR-T细胞功效所需的。此外，通过 IL-1 R增强IL-6产生，因此阻断IL-1 R具有阻断IL-6产生的潜力， 下游的后果。我们正在开展一项2期单中心开放标签研究， 以及阿那白滞素与axicabtagene ciloleucel联合治疗复发性或难治性NHL患者的疗效。 我们的假设是，阻断IL-1 R信号传导将阻止2级或更高级别的NTX和CRS的发展， 并且这在临床上以及通过调节细胞因子和免疫细胞的相关证据将是明显的 在外周血和脑脊液（CSF）中的相互作用。Maus博士（PI）将持有IND， Frigault（co-I）将担任临床研究者，Kite Pharma将提供药物（axi-cel和阿那白滞素）， 并为临床研究提供部分资金支持。我们寻求NIH资金（此R 01提案）用于工资支持 为临床研究的研究者提供信息，并进行相关研究，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， 以及蛋白质上T细胞和髓样细胞区室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， 免疫相互作用的影响。我们将使用来自接受以下治疗的患者的样本： 市售的axicabtagene ciloleucel作为比较物。这项研究的完成意义重大，因为它可以 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.