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嵌合抗原受体 T 细胞毒性:从床边到实验室,新型毒性如何为实验室研究提供信息。

CAR T-cell toxicities: from bedside to bench, how novel toxicities inform laboratory investigations.

机构信息

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL.

Division of Hematology and Medical Oncology, The Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

出版信息

Blood Adv. 2024 Aug 27;8(16):4348-4358. doi: 10.1182/bloodadvances.2024013044.


DOI:10.1182/bloodadvances.2024013044
PMID:38861351
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11375260/
Abstract

Multiple chimeric antigen receptor (CAR) T-cell therapies are US Food and Drug Administration-approved, and several are under development. Although effective for some cancers, toxicities remain a limitation. The most common toxicities, that is, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, are well described. With increasing utilization, providers worldwide are reporting other emergent and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalog these emerging and emergent CAR T-cell toxicities and describe management approaches, the American Society of Hematology Subcommittee on Emerging Gene and Cell Therapies organized the first scientific workshop on CAR T-cell toxicities during the annual society meeting. The workshop functioned to (1) aggregate reports of CAR T-cell emergent toxicities, including movement disorders after B-cell maturation antigen CAR T cell, coagulation abnormalities, and prolonged cytopenia; (2) disseminate bedside-to-bench efforts elucidating pathophysiological mechanisms of CAR T-cell toxicities, including the intestinal microbiota and systemic immune dysregulation; and (3) highlight gaps in the availability of clinical tests, such as cytokine measurements, which could be used to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, although clinical manifestations may develop before the pathophysiologic mechanisms are understood, they must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears to be central to these emergent toxicities, and research is needed to elucidate the links between tumors, CAR T cells, and microbiota. Finally, there was a consensus around the urgency to create a repository to capture emergent CAR T-cell toxicities and the real-world management.

摘要

多种嵌合抗原受体 (CAR) T 细胞疗法已获得美国食品和药物管理局批准,并且正在开发几种。尽管对某些癌症有效,但毒性仍然是一个限制。最常见的毒性,即细胞因子释放综合征和免疫效应细胞相关神经毒性综合征,已有详细描述。随着越来越多的应用,全球的提供者正在报告其他新出现的且常常复杂的毒性。鉴于不断发展的毒性特征以及迫切需要对这些新出现和新兴的 CAR T 细胞毒性进行编目并描述管理方法,美国血液学会新兴基因和细胞治疗学小组委员会在年度学会会议期间组织了第一次关于 CAR T 细胞毒性的科学研讨会。该研讨会的功能是:(1) 汇总 CAR T 细胞新出现毒性的报告,包括 B 细胞成熟抗原 CAR T 细胞后运动障碍、凝血异常和长期细胞减少症;(2) 传播阐明 CAR T 细胞毒性病理生理机制的床边到床边的努力,包括肠道微生物群和全身免疫失调;(3) 强调临床测试(如细胞因子测量)可用性方面的差距,这可用于扩展我们对毒性监测的了解。出现了一些关键主题。首先,尽管临床表现可能在了解病理生理机制之前就已经出现,但必须对其进行研究,以帮助检测和预防此类毒性。其次,全身免疫失调似乎是这些新出现的毒性的核心,需要研究来阐明肿瘤、CAR T 细胞和微生物群之间的联系。最后,人们一致认为迫切需要创建一个存储库来捕获新出现的 CAR T 细胞毒性和真实世界的管理。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa8/11375260/847d380cd951/BLOODA_ADV-2024-013044-ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa8/11375260/847d380cd951/BLOODA_ADV-2024-013044-ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa8/11375260/847d380cd951/BLOODA_ADV-2024-013044-ga1.jpg

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引用本文的文献

[1]
CAR-T cell therapy in brain malignancies: obstacles in the face of cellular trafficking and persistence.

Front Immunol. 2025-6-19

[2]
CAR T cell therapy for children with rheumatic disease: the time is now.

Nat Rev Rheumatol. 2025-7-2

[3]
Neurological complications of CAR T cell therapy for cancers.

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[4]
Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy.

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[5]
Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia.

Transplant Cell Ther. 2025-5-20

[6]
CAR T-cell therapy in renal cell carcinoma: opportunities, challenges, and new strategies to overcome.

Med Oncol. 2025-4-24

[7]
Celebrating a year of immunotherapy/cell and gene therapy in Blood Advances.

Blood Adv. 2024-12-24

本文引用的文献

[1]
Need for standardization of cytokine profiling in CAR T cell therapy.

Mol Ther. 2024-9-4

[2]
Unanswered questions following reports of secondary malignancies after CAR-T cell therapy.

Nat Med. 2024-2

[3]
INSPIRED Symposium Part 4B: Chimeric Antigen Receptor T Cell Correlative Studies-Established Findings and Future Priorities.

Transplant Cell Ther. 2024-2

[4]
Cooperative CAR targeting to selectively eliminate AML and minimize escape.

Cancer Cell. 2023-11-13

[5]
Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.

Sci Adv. 2023-9-22

[6]
Emapalumab for the treatment of refractory cytokine release syndrome in pediatric patients.

Blood Adv. 2023-9-26

[7]
The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

J Hematol Oncol. 2023-7-31

[8]
A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Cell Rep Med. 2023-7-18

[9]
Chemotherapy-induced reversal of ciltacabtagene autoleucel-associated movement and neurocognitive toxicity.

Blood. 2023-10-5

[10]
CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results.

Nat Med. 2023-7

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