肿瘤细胞治疗研究
英文原题：Clinical presentation, management, and outcome of TIAN in CNS lymphoma treated with CD19-CAR T-cell therapy.
Clinical presentation, management, and outcome of TIAN in CNS lymphoma treated with CD19-CAR T-cell therapy.
我们的工作支持将TIAN视为一种局限性的、发生于肿瘤部位的、靶向性神经毒性综合征，与既有的CNSL病灶密切相关，且不同于ICANS。
肿瘤炎症相关神经毒性（TIAN）最近被提出为脑肿瘤患者免疫治疗的一种独特并发症。在此，我们首次对接受CD19靶向嵌合抗原受体（CD19-CAR）T细胞治疗的中枢神经系统（CNS）淋巴瘤（CNSL）患者中TIAN进行了全面的特征描述。TIAN发生于56例CNSL患者中的10例（17.9%），临床起病中位时间为CD19-CAR T细胞输注后3.5天（范围，1-9天）。与免疫效应细胞相关神经毒性综合征（ICANS）相比，TIAN与细胞因子释放综合征的关联频率较低（60% vs 100%；P = .009）。尽管症状通常为一过性且完全可逆，但TIAN与1例患者的致死性结局相关。基线时较大的CNS肿瘤体积有助于识别有TIAN风险的患者（曲线下面积，0.847；P = .002）。最大化Youden J统计量后，确定了>3.4 cm3的判别性肿瘤体积阈值，其敏感性为87.5%，特异性为80.5%。在多变量Cox比例风险回归中，TIAN与CD19-CAR T细胞更高的总缓解率相关（90% vs 52%；P = .036），并与改善的无进展生存期相关（风险比，0.22；95%置信区间，0.07-0.61；P = .006）。对一处TIAN病灶的死后组织病理学评估显示，密集的巨噬细胞群伴中心坏死和外周反应性胶质增生，并伴有白质丢失和泡沫状巨噬细胞内胞质髓鞘。总之，我们的工作支持将TIAN视为一种局限于肿瘤的、靶向性神经毒性综合征，与既有的CNSL病灶密切相关，且不同于ICANS。基线时CNS肿瘤体积可能有助于识别有风险的患者，并可能指导管理。
Tumor inflammation-associated neurotoxicity (TIAN) was recently proposed as a unique complication of immunotherapy in patients with brain tumor. Here, we report a first comprehensive characterization of TIAN in patients with central nervous system (CNS) lymphoma (CNSL) treated with CD19-directed chimeric antigen receptor (CD19-CAR) T cells. TIAN occurred in 10 of 56 (17.9%) patients with CNSL, with clinical onset at a median 3.5 days (range, 1-9) after CD19-CAR T-cell infusion. It was less frequently associated with cytokine release syndrome (60% vs 100%; P = .009) than immune effector cell-associated neurotoxicity syndrome (ICANS). Although symptoms were usually transient and fully reversible, TIAN was associated with a fatal outcome in 1 patient. Larger CNS tumor volume at baseline allowed the identification of patients at risk for TIAN (area under the curve, 0.847; P = .002). Maximizing Youden J statistics, a discriminatory tumor volume threshold of >3.4 cm3 was determined, which carried 87.5% sensitivity and 80.5% specificity. TIAN correlated with higher overall response rates to CD19-CAR T cells (90% vs 52%; P = .036) and improved progression-free survival (hazard ratio, 0.22; 95% confidence interval, 0.07-0.61; P = .006) on multivariate Cox proportional hazard regression. Postmortem histopathological evaluation of a TIAN lesion revealed a dense macrophage population with central necrosis and peripheral reactive gliosis, accompanied by loss of white matter and intracytoplasmic myelin in foamy macrophages. Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to preexisting CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management.
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