Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell–independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell–dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro , and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. Significance: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.

中文翻译：

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T细胞与内皮细胞的粘附促进Blinatumomab相关的神经系统不良事件。

Blinatumomab是用于治疗B细胞恶性肿瘤的CD19 / CD3双特异性T细胞接合剂（BiTE）免疫肿瘤疗法，与亚组患者的神经系统不良事件相关。在这里，我们提供了针对由blinatumomab引起的神经系统不良事件发展的两步过程的证据：（i）blinatumomab诱导的周围T细胞的B细胞非依赖性重新分布，包括T细胞对血管内皮，内皮细胞的粘附激活和T细胞向血管周围的迁移，（ii）blinatumomab诱导依赖B细胞的T细胞激活和细胞因子释放，从而可能触发神经系统不良事件。该过程的证据包括（i）T细胞重新分布的同时发生以及大多数神经系统不良事件的早期发生，（ii）通过脑微血管内皮细胞进行T细胞迁移，（iii）检测脑脊液中的T细胞，B细胞和blinatumomab，（iv）体外blinatumomab诱导的T细胞滚动和粘附于血管内皮细胞，和（ v）在体外和患者中抗粘连剂干扰blinatumomab诱导的T细胞和血管内皮细胞之间相互作用的能力。基于这些观察，我们提出了一种模型，该模型可以作为与blinatumomab治疗和其他T细胞疗法相关的神经系统不良事件的缓解策略的基础。启示：这项研究提出T细胞对内皮细胞的粘附是发展与blinatumomab相关的神经系统不良事件的必要但不充分的第一步，并建议作为一种缓解方法来干扰粘附。