Department of Stem Cell Transplantation; Research Department Cell and Gene Therapy.
Department of Hematology/Oncology.
Haematologica. 2023 Feb 1;108(2):444-456. doi: 10.3324/haematol.2022.281110.
CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.
CD19 特异性嵌合抗原受体 (CD19-CAR) T 细胞疗法可介导晚期 B 细胞恶性肿瘤的持久缓解，但可能会出现严重的免疫效应细胞相关神经毒性综合征 (ICANS)。尽管进行了广泛的努力，但 ICANS 的确切机制仍不完全清楚，并且已经观察到对当前针对 ICANS 的治疗方法（尤其是皮质类固醇）的耐药性。最近的数据表明，炎症细胞因子和/或针对大脑 CD19 表达的周细胞的靶向作用可能会破坏血脑屏障并促进免疫细胞（包括 CAR T 细胞）的涌入。然而，在通常是微量的脑脊液 (CSF) 样本中针对 CD19-CAR T 细胞分析的特定工具并不广泛可用。在这里，我们应用我们最近开发的数字聚合酶链反应检测法来监测具有神经毒性的真实患者的 CSF 和血液中的 CD19-CAR T 细胞动力学。一致地，我们观察到在 ICANS 患者的 CSF 中存在 CAR T 细胞富集，尽管在一组对皮质类固醇含量高的免疫化学疗法有反应的患者中进行了强化治疗，但仍存在进行性积累。我们使用下一代 T 细胞受体-β测序来评估治疗抵抗细胞的库。纵向分析显示 T 细胞受体库的明显倾斜，至少部分反映了输注 T 细胞克隆的选择性扩增。有趣的是，最终占主导地位的过度扩增 T 细胞克隆的主要部分来自非 CAR T 细胞。这些发现暗示了治疗抵抗性 T 细胞克隆在严重的 ICANS 发展中的作用，并促使未来进行系统研究以确定 CAR T 细胞是否可以作为“开门器”，并进一步对 CAR 阳性和非 CAR T 细胞进行特征分析，以研究这些可能病理性 T 细胞的转录特征。
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