Targeting Myeloid Cells to Mitigate Immune Effector Cell-Associated Neurotoxicity Syndrome in Large B-cell Lymphoma

靶向骨髓细胞减轻大 B 细胞淋巴瘤中免疫效应细胞相关的神经毒性综合征

• 批准号: 10198526
• 负责人: Michael Richard Green
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198526
• 关键词: Acute Lymphocytic Leukemia; Adrenal Cortex Hormones; Affect; Autologous; B-Cell Lymphomas; Biology; Blocking Antibodies; Blood specimen; CAR T cell therapy; CD19 gene; Cell physiology; Cells; Cessation of life; Clinical; Color; Correlative Study; Data; Development; Disease remission; Dose; Effector Cell; FDA approved; Financial Hardship; Financial cost; Flow Cytometry; Follicular Lymphoma; Frequencies; Genes; Healthcare; Healthcare Systems; Hospitalization; Hospitals; Immune; In complete remission; Incidence; Inflammatory; Infusion procedures; Intensive Care; Interleukin 6 Receptor; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Measures; Mediator of activation protein; Monoclonal Antibodies; Morbidity - disease rate; Multiple Myeloma; Myeloid Cells; Names; Neurotoxicity Syndromes; Patients; Phenotype; Plasma; Pre-Clinical Model; Production; Prophylactic treatment; Refractory; Rehabilitation therapy; Relapse; Reporting; Resources; Safety; Serum; T-Lymphocyte; Testing; Time; Toxic effect; acute toxicity; anakinra; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; cohort; cytokine; cytokine release syndrome; improved; mortality; multiplex assay; novel; novel strategies; patient subsets; peripheral blood; prevent; prophylactic; response; single-cell RNA sequencing; tocilizumab

Project Summary The unprecedented efficacy of chimeric antigen receptor (CAR) modified T cells, for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), is limited by significant toxicities, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) being reported in up to 90% and 70% of patient, respectively. While the biology of CRS has been extensively investigated and tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is available for its treatment, ICANS is largely managed by a broad immunosuppressive strategy using corticosteroids, which may affect CAR T-cell function. To this regard, we found that early and higher cumulative dose of corticosteroids is associated with early progression and death after axi-cel, highlighting the need for development of novel and corticosteroid-sparing strategies that target the underlying mechanism of ICANS. Pre-clinical models show that IL-1 blockade through anakinra, an IL-1 receptor antagonist, can effectively mitigate ICANS. Our analysis of CAR-T-treated LBCL patients shows that serum IL-1 peaks within the first 7 days after axi-cel infusion. In addition, we also observed that the infusion product of patients who develop ICANS has higher frequency of myeloid cells (named ICANS- associated cells or IACs), which expressed multiple cytokine and chemokine genes including IL-1. Importantly, patients with IACs detected within their infusion products had higher levels of inflammatory cytokines in their serum including IL-1 following infusion compared to patients with no IACs. Taken together, these data provided rationale to evaluate anakinra as a prophylactic strategy to mitigate ICANS after CAR T-cell therapy. Our central hypothesis is that IL-1 blockade using anakinra, an IL-1 receptor antagonist, will reduce the frequency of ICANS in r/r LBCL patients treated with axi-cel without impacting CAR T-cell expansion or efficacy and, that the benefit of anakinra will be observed primarily in patients treated with CAR-T infusion products containing IACs. Our specific aims are: 1) to investigate the effects of anakinra on ICANS and CAR T-cell activity, and 2) to determine whether prophylactic anakinra mitigates production of inflammatory cytokines in patients receiving CAR-T products containing IACs. We will test this by comparing the rates of ICANS and clinical response rates between two cohorts of patients: (i) 20 patients treated with prophylactic anakinra following axi-cel therapy, and (ii) a contemporaneous cohort of 20 patients treated with axi-cel without anakinra prophylaxis. Serial peripheral blood samples will be analyzed to determine the effects of anakinra on CAR T-cell amplification and phenotype. Plasma cytokines and chemokines will be assessed by multiplex assays, to determine the effects on anakinra on inflammatory molecules. The infusion products will be analyzed by 24-color spectral flow cytometry and single cell RNA-sequencing to determine the frequency of IACs.

项目摘要 嵌合抗原受体（CAR）修饰的T细胞的前所未有的功效，用于治疗患者 具有复发或难治性的大B细胞淋巴瘤（LBCL），受到明显毒性的限制，细胞因子释放 综合征（CRS）和免疫效应子细胞相关的神经毒性综合征（ICAN）被报告为 分别为90％和70％的患者。虽然CRS的生物学已经进行了广泛的研究，并且 Tocilizumab是一种靶向IL-6受体的单克隆抗体，可用于治疗，ICAN在很大程度上是 由使用皮质类固醇的广泛免疫抑制策略管理，这可能会影响汽车T细胞功能。 在这方面，我们发现皮质类固醇的早期和更高累积剂量与早期有关 AXI-CEL后的进展和死亡，强调了新型和皮质类固醇的发展的需求 针对ICANS基本机制的策略。临床前模型表明IL-1通过 IL-1受体拮抗剂Anakinra可以有效地减轻ICANS。我们对CAR-T处理LBCL的分析 患者表明，血清IL-1在AXI-CEL输注后的前7天内达到峰值。另外，我们还观察到 发育ICAN的患者的输注产物具有较高的髓样细胞的频率（称为ICANS- 相关细胞或IACS），该细胞表达了包括IL-1在内的多种细胞因子和趋化因子基因。重要的是， 在输液产品中检测到IACS的患者的炎性细胞因子水平较高 与无IACS患者相比，输注后包括IL-1在内的血清。综上所述，提供了这些数据 评估Anakinra作为一种预防性策略来减轻ICAN的理由，以减轻T细胞治疗后的ICANS。我们的中心 假设是使用IL-1受体拮抗剂Anakinra的IL-1阻断将降低ICAN的频率 在接受AXI-CEL治疗的R/R LBCL患者中，没有影响CAR T细胞的扩展或功效，并且有益于 Anakinra将主要观察到用含有IACS的CAR-T输注产品治疗的患者。我们的 具体目的是：1）研究Anakinra对ICAN和CAR T细胞活动的影响，以及2）确定 预防性anakinra是否会减轻接受CAR-T的患者的炎性细胞因子的产生 包含IACS的产品。我们将通过比较ICAN的速率和临床反应率来测试这一点 两名患者组：（i）20患者在AXI-CEL治疗后接受预防性Anakinra治疗的患者，以及（ii）A 同时的20例接受Anakinra预防的AXI-CEL治疗的患者的同时人群。串行外周血 将分析样品，以确定Anakinra对CAR T细胞扩增和表型的影响。等离子体 细胞因子和趋化因子将通过多重测定评估，以确定对Anakinra的影响 炎症分子。输注产物将通过24色光流式细胞仪和单一分析 细胞RNA测序以确定IACS的频率。

项目成果

A single-cell atlas of CD19 chimeric antigen receptor T cells.

CD19 嵌合抗原受体 T 细胞的单细胞图谱。

• DOI: 10.1016/j.ccell.2023.08.015
• 发表时间: 2023
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Li,Xubin;Henderson,Jared;Gordon,MaxJ;Sheikh,Irtiza;Nastoupil,LorettaJ;Westin,Jason;Flowers,Christopher;Ahmed,Sairah;Wang,Linghua;Neelapu,SattvaS;Strati,Paolo;Deng,Qing;Green,MichaelR
• 通讯作者: Green,MichaelR