Del Duca Fabio, Napoletano Gabriele, Volonnino Gianpietro, Maiese Aniello, La Russa Raffaele, Di Paolo Marco, De Matteis Serena, Frati Paola, Bonafè Massimiliano, Fineschi Vittorio
Department of Anatomical, Histological, Forensic and Orthopedical Sciences, Sapienza University of Rome, Rome, Italy.
Section of Legal Medicine, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
Front Med (Lausanne). 2024 Jan 8;10:1272291. doi: 10.3389/fmed.2023.1272291. eCollection 2023.
CAR-T-related deaths observed worldwide are rare. The underlying pathogenetic mechanisms are the subject of study, as are the findings that enable diagnosis. A systematic literature search of the PubMed database and a critical review of the collected studies were conducted from the inception of this database until January 2023. The aim of the study is to determine when death is related to CAR-T cell therapy and to develop a shareable diagnostic algorithm.
The database was searched by combining and meshing the terms ("CAR-t" OR "CART") AND ("Pathology" OR "Histology" OR "Histological" OR "Autopsy") AND ("Heart" OR "Cardiac" OR "Nervous System" OR "Kidney" OR "Liver") with 34 results and also the terms: [(Lethal effect) OR (Death)] AND (CAR-T therapy) with 52 results in titles, abstracts, and keywords [all fields]. One hundred scientific articles were examined, 14 of which were additional records identified through other sources. Fifteen records were included in the review.
Neuronal death, neuronal edema, perivascular edema, perivascular and intraparenchymal hemorrhagic extravasation, as well as perivascular plasmatodendrosis, have been observed in cases with fatal cerebral edema. A cross-reactivity of CAR-T cells in cases of fatal encephalopathy can be hypothesized when, in addition to the increased vascular permeability, there is also a perivascular lymphocyte infiltrate, which appears to be a common factor among most authors.
Most CAR-T-related deaths are associated with blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells. Further autopsies and microscopic investigations would shed more light on the lethal toxicity related to CAR-T cells. A differential diagnosis of CAR-T-related death is crucial to identifying adverse events. In this article, we propose an algorithm that could facilitate the comparison of findings through a systematic approach. Despite toxicity cases, CAR-T therapy continues to stand out as the most innovative treatment within the field of oncology, and emerging strategies hold the promise of delivering safer therapies in future.
全球范围内观察到的与嵌合抗原受体T细胞（CAR-T）相关的死亡病例较为罕见。其潜在的发病机制以及能够实现诊断的相关发现均是研究的主题。从PubMed数据库建立之初至2023年1月，我们对该数据库进行了系统的文献检索，并对所收集的研究进行了批判性综述。本研究的目的是确定死亡何时与CAR-T细胞疗法相关，并开发一种可共享的诊断算法。
通过将术语（“CAR-t”或“CART”）与（“病理学”或“组织学”或“组织学的”或“尸检”）以及（“心脏”或“心脏的”或“神经系统”或“肾脏”或“肝脏”）进行组合和筛选，在数据库中检索到34条结果；同时，在标题、摘要和关键词[所有字段]中，将术语[（致死效应）或（死亡）]与（CAR-T疗法）进行检索，得到52条结果。共审查了100篇科学文章，其中14篇是通过其他来源确定的额外记录。15条记录被纳入综述。
在致命性脑水肿病例中观察到神经元死亡、神经元水肿、血管周围水肿、血管周围和脑实质内出血性外渗以及血管周围浆细胞增多。在致命性脑病病例中，可以推测CAR-T细胞存在交叉反应性，此时除了血管通透性增加外，还存在血管周围淋巴细胞浸润，这似乎是大多数作者研究中的一个共同因素。
大多数与CAR-T相关的死亡与血脑屏障破坏、中枢神经系统细胞损伤和浸润的T细胞有关。进一步的尸检和显微镜检查将更清楚地揭示与CAR-T细胞相关的致死毒性。对与CAR-T相关死亡进行鉴别诊断对于识别不良事件至关重要。在本文中，我们提出了一种算法，该算法可以通过系统的方法促进对各项发现的比较。尽管存在毒性病例，但CAR-T疗法仍然是肿瘤学领域最具创新性的治疗方法，新出现的策略有望在未来提供更安全的治疗方法。
