在接受CAR-T细胞治疗后，患者有时会告诉医生，他们感觉自己出现了“脑雾”，即健忘和注意力难以集中。

After treatment with CAR-T cells patients sometimes tell their doctors they feel like they have "brain fog," or forgetfulness and difficulty concentrating.

一项由斯坦福大学医学院主导的新研究表明，CAR-T细胞疗法会导致轻度认知障碍，而这种情况是通过与其他两种原因（化疗，流感和COVID-19等呼吸道感染）引起的认知障碍相同的细胞机制发生的。

A new Stanford Medicine-led study shows that CAR-T cell therapy causes mild cognitive impairments and that this happens via the same cellular mechanism as cognitive impairment from two other causes: chemotherapy and respiratory infections such as flu and COVID-19.

研究人员说，改善脑雾的药物将使癌症免疫治疗后更好地恢复。

Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers said.

CAR-T细胞治疗后的认知损伤通常是轻微的。

Cognitive impairment after CAR-T cell therapy is typically mild.

但这是令人沮丧的，可能不会自行解决，Monje说。

But it is frustrating and may not resolve on its own, Monje said.

在CAR-T细胞治疗前后，研究人员对小鼠进行了标准的认知测试，测量小鼠对新物体的反应以及在简单的迷宫中行走的情况。

Before and after CAR-T cell treatment, the re-searchers used standard cognitive tests on the mice, measuring how mice responded to a novel object and navigated a simple maze.

在CAR-T治疗后，CAR-T细胞会引起炎症。

The CAR-T treatment causes minimal additional inflammation.

研究人员证明，小胶质细胞是这个问题的关键。

The researchers demonstrated that the brain's immune cells, called microglia, are key players in the problem.

被激活的小胶质细胞产生炎症免疫分子，即细胞因子和趋化因子，它们反过来在整个大脑中产生广泛的影响。

The activated, "annoyed" microglia pro-duce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects throughout the brain.

它们对少突胶质细胞尤其有害，少突胶质细胞是负责制造髓磷脂的脑细胞，髓磷脂是一种脂肪物质，可以隔离神经纤维，帮助神经更有效地传递信号。

They are particularly harmful for oligodendrocytes, the brain cells responsible for making myelin, the fatty substance that insulates nerve fibers and helps nerves transmit signals more efficiently.

神经绝缘的减少会导致认知障碍。

Reduction in the nerves' insulation translates into cognitive impairment.

科学家们还分析了参与该团队正在进行的CAR-T细胞治疗脊髓和脑干肿瘤临床试验的人类受试者的脑组织样本。

The scientists also analyzed samples of brain tissue from human subjects who participated in the team's ongoing clinical trial of CAR-T cells for spinal cord and brain stem tumors.

利用死后组织样本，研究人员证实，小胶质细胞和少突胶质细胞出现了失调，这与他们在CAR-T治疗后的小鼠身上观察到的情况相同。

Using postmortem tissue samples, the re-searchers confirmed that microglia and oligodendrocytes appear dysregulated in the same way the team had ob-served in mice after CAR-T therapy.

研究小组在鼠身上测试了解决认知问题的策略。

In mice, the research team tested strategies to resolve the cognitive problems.

他们给了一种化合物，在两周的时间里耗尽了鼠大脑中的小胶质细胞。

They gave a compound that depleted microglia in the brains of the mice for a two-week period.

这些小鼠不再有认知障碍。

The mice were no longer cognitively impaired.

研究人员还给老鼠注射了一种药物，这种药物可以进入大脑，干扰来自有害趋化因子的信号，阻断这些分子的特定受体。

The researchers also gave the mice a medication that en-ters the brain and interferes with signals from damaging chemokines, blocking a specific receptor for these molecules.

Monje说：“这也就拯救了认知能力。”他补充说，研究人员正在探索如何安全地将这两种策略——短暂消耗小胶质细胞或中断趋化因子信号——转化为接受过CAR-T细胞治疗的人。

"That alone rescued cognition," Monje said, adding that the researchers are now exploring how to safely translate the two strategies -- transiently depleting microglia or in-terrupting chemokine signals -- in people who have had CAR-T cell therapy.

Journal Reference:

1. Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel B. Zamler, Lijun Ni, Kevin Cross, Justin Rustenhoven, Jonathan Kipnis, Shane A. Liddelow, Crystal L. Mackall, Robbie G. Majzner, Michelle Monje. Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. Cell, 2025; DOI: 10.1016/j.cell.2025.03.041