Driscoll David F, Bistrian Bruce R
Stable Solutions LLC, Easton, MA, United States.
Department of Medicine, UMASS Chan Medical School, Worcester, MA, United States.
Front Pharmacol. 2025 Jun 10;16:1615526. doi: 10.3389/fphar.2025.1615526. eCollection 2025.
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.
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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