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.

项目概要 嵌合抗原受体 (CAR) 修饰 T 细胞在治疗患者方面具有前所未有的功效 患有复发性或难治性大 B 细胞淋巴瘤 (LBCL) 的患者，受到显着毒性的限制，并伴有细胞因子释放 综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）的报告最多 分别为 90% 和 70% 的患者。虽然 CRS 的生物学已被广泛研究并 托珠单抗（tocilizumab）是一种针对 IL-6 受体的单克隆抗体，可用于其治疗，ICANS 很大程度上 通过使用皮质类固醇的广泛免疫抑制策略进行管理，这可能会影响 CAR T 细胞功能。 在这方面，我们发现早期和较高的皮质类固醇累积剂量与早期 axi-cel 后的进展和死亡，凸显了开发新型且节省皮质类固醇的药物的必要性 针对 ICANS 基本机制的策略。临床前模型表明 IL-1 阻断通过 阿那白滞素 (anakinra) 是一种 IL-1 受体拮抗剂，可有效缓解 ICANS。我们对 CAR-T 治疗的 LBCL 的分析 患者的血清 IL-1 在 axi-cel 输注后的前 7 天内达到峰值。此外，我们还观察到 发生 ICANS 的患者的输注产品具有较高频率的骨髓细胞（命名为 ICANS- 相关细胞或 IAC），表达多种细胞因子和趋化因子基因，包括 IL-1。重要的是， 在输液产品中检测到 IAC 的患者体内炎症细胞因子水平较高 与未注射 IAC 的患者相比，输注后血清中含有 IL-1。综合起来，这些数据提供了 评估阿那白滞素作为 CAR T 细胞治疗后减轻 ICANS 的预防策略的基本原理。我们的中央 假设使用阿那白滞素（一种 IL-1 受体拮抗剂）阻断 IL-1，会降低 ICANS 的频率 在接受 axi-cel 治疗的 r/r LBCL 患者中，不影响 CAR T 细胞扩增或疗效，并且获益 阿那白滞素的作用主要在接受含有 IAC 的 CAR-T 输注产品治疗的患者中观察到。我们的 具体目标是：1) 研究阿那白滞素对 ICANS 和 CAR T 细胞活性的影响，以及 2) 确定 预防性阿那白滞素是否会减轻接受 CAR-T 治疗的患者炎症细胞因子的产生 含有 IAC 的产品。我们将通过比较 ICANS 率和临床反应率来测试这一点 两组患者：(i) 20 名患者在 axi-cel 治疗后接受预防性阿那白滞素治疗，以及 (ii) 由 20 名接受 axi-cel 治疗但未进行阿那白滞素预防的患者组成的同期队列。连续外周血 将分析样品以确定阿那白滞素对 CAR T 细胞扩增和表型的影响。等离子体 将通过多重测定评估细胞因子和趋化因子，以确定对阿那白滞素的影响 炎症分子。输液产品将通过24色光谱流式细胞术和单 细胞 RNA 测序以确定 IAC 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。

• 发表时间: 2023-11-13
• 影响因子: 50.3
• 作者: Li, Xubin;Henderson, Jared;Gordon, Max J;Sheikh, Irtiza;Nastoupil, Loretta J;Westin, Jason;Flowers, Christopher;Ahmed, Sairah;Wang, Linghua;Neelapu, Sattva S;Strati, Paolo;Deng, Qing;Green, Michael R
• 通讯作者: Green, Michael R