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细胞因子释放综合征与嵌合抗原受体T细胞疗法:调节肿瘤微环境中炎症反应的强度及消退

Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.

作者信息

Driscoll David F, Bistrian Bruce R

机构信息

Stable Solutions LLC, Easton, MA, United States.

Department of Medicine, UMASS Chan Medical School, Worcester, MA, United States.

出版信息

Front Pharmacol. 2025 Jun 10;16:1615526. doi: 10.3389/fphar.2025.1615526. eCollection 2025.


DOI:10.3389/fphar.2025.1615526
PMID:40556762
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12186451/
Abstract

CAR T cell therapy achieves high degrees of success with respect to complete response and overall response rates in many hematological cancers, especially lymphomas. Compared to other immunotherapies, these "activated" blood products are plagued by a high incidence of a severe systemic inflammatory response syndrome, resulting from the exaggerated release of cytokines, chemokines, and other pro-inflammatory protein and lipid mediators. These can produce what is known as the "cytokine release syndrome" (CRS), associated with significant morbidity and mortality. Although successful CAR T cell therapy reduces the tumor load, the killing of large numbers of cancer cells and the persistence of apoptotic cellular debris within the tumor microenvironment (TME) may also be tumorigenic. We propose a single active pharmaceutical ingredient (API), the highly polyunsaturated omega-3 fatty acids eicosapentaenoic and docosahexaenoic acids, applying a refined and enriched fish oil, with multiple therapeutic targets that can be administered in precise doses. First, they rapidly modulate the intensity of the systemic inflammatory response, by modifying eicosanoid metabolism via intravenous administration. Second, as substrates for the production of specialized pro-resolving mediators (SPMs) of inflammation, they can help clear cellular debris within the TME, perhaps reducing the risks of new tumor formation. The employment of such a drug either in a prophylactic and/or a treatment manner might further improve the outcome of CAR T cell therapy.

摘要

嵌合抗原受体(CAR)T细胞疗法在许多血液系统癌症,尤其是淋巴瘤的完全缓解率和总体缓解率方面取得了很高的成功率。与其他免疫疗法相比,这些“活化的”血液制品存在严重全身炎症反应综合征的高发生率问题,这是由细胞因子、趋化因子以及其他促炎蛋白和脂质介质的过度释放所导致的。这些物质会引发所谓的“细胞因子释放综合征”(CRS),并伴有显著的发病率和死亡率。尽管成功的CAR T细胞疗法降低了肿瘤负荷,但大量癌细胞的杀伤以及肿瘤微环境(TME)中凋亡细胞碎片的持续存在也可能具有致瘤性。我们提出一种单一活性药物成分(API),即高度多不饱和的ω-3脂肪酸二十碳五烯酸和二十二碳六烯酸,采用经过精制和富集的鱼油,它具有多个治疗靶点,且可以精确剂量给药。首先,通过静脉给药改变类花生酸代谢,它们能迅速调节全身炎症反应的强度。其次,作为炎症特异性促消退介质(SPM)产生的底物,它们有助于清除TME内的细胞碎片,或许能降低新肿瘤形成的风险。以预防和/或治疗方式使用这种药物可能会进一步改善CAR T细胞疗法的疗效。

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本文引用的文献

[1]
Chimeric antigen receptor-macrophages: Emerging next-generation cell therapy for brain cancer.

Neurooncol Adv. 2025-3-19

[2]
Cell-based immunotherapies for solid tumors: advances, challenges, and future directions.

Front Oncol. 2025-4-28

[3]
Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome.

PLoS Comput Biol. 2025-4-9

[4]
Cytokine Storms in COVID-19, Hemophagocytic Lymphohistiocytosis, and CAR-T Therapy.

JAMA Netw Open. 2025-4-1

[5]
Omega-3 Polyunsaturated Fatty Acids in Sepsis: From Prevention to Early Treatment.

Crit Care Med. 2025-3-3

[6]
The role of non-malignant B cells in malignant hematologic diseases.

Hematology. 2025-12

[7]
Hemophagocytic Lymphohistiocytosis.

N Engl J Med. 2025-2-6

[8]
Association of Omega-3 Status With Long-Term Risk of Hospitalization for Sepsis.

Crit Care Med. 2025-2-3

[9]
Exploring the unique role of specialized pro-resolving mediators in cancer therapeutics.

Prostaglandins Other Lipid Mediat. 2025-6

[10]
The current socioeconomic and regulatory landscape of immune effector cell therapies.

Front Med (Lausanne). 2024-12-4

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