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

项目摘要 嵌合抗原受体(CAR)修饰的T细胞对患者的治疗效果前所未有 复发或难治性大B细胞淋巴瘤(LBCL)，毒性有限，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)在多达 分别为90%和70%。虽然CRS的生物学已经被广泛研究并 针对IL-6受体的单抗tocilizumab可用于治疗，icans在很大程度上 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。 在这一点上，我们发现早期和较高的皮质类固醇累积剂量与早期 轴突后的进展和死亡，突出了开发新的和非皮质类固醇的必要性 以ICAN基本机制为目标的战略。临床前模型显示IL-1通过 IL-1受体拮抗剂Anakinra可以有效缓解ICAN。我们对CAR-T治疗LBCL的分析 患者显示，血清IL-1在轴索注射后的头7天内达到峰值。此外，我们还观察到 患有ICANs的患者的输液产品中有较高的髓系细胞频率(称为ICANS- 相关细胞或IAC)，表达包括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IAC的患者，其体内的炎性细胞因子水平较高 输注后包括IL-1在内的血清与无IAC的患者比较。总而言之，这些数据提供了 评估Anakinra作为CAR T细胞治疗后缓解ICAN的预防性策略的理由。我们的中央 假设使用IL-1受体拮抗剂Anakinra阻断IL-1将减少ICAN的发生频率 在r/r LBCL患者中，AXAXCEL在不影响CAR T细胞增殖或疗效的情况下，其益处 阿纳金拉的发生将主要在接受含有IAC的CAR-T输液产品治疗的患者中观察到。我们的 具体目标是：1)研究Anakinra对ICAN和CAR T细胞活性的影响；2)确定 预防性使用Anakinra是否能减轻接受CAR-T治疗的患者炎性细胞因子的产生 含有IAC的产品。我们将通过比较ICAN的发生率和临床反应率来测试这一点 两个队列的患者：(I)20名患者在轴突治疗后预防性使用anakinra治疗，以及(Ii)a 20例同期接受AXICEL治疗但未预防Anakinra的患者的队列。连续外周血 将对样本进行分析，以确定Anakinra对CAR T细胞扩增和表型的影响。电浆 细胞因子和趋化因子将通过多重分析进行评估，以确定对Anakinra的影响 炎性分子。输液产品将用24色光谱流式细胞仪和单色 细胞RNA测序以确定IAC的频率。

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.