Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.
Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.
复制标题
CAR-T 细胞活性的提高与半乳糖引发的线粒体功能的增强相关。
DOI：
10.1101/2023.09.23.559091
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Jacoby,Elad
中科院分区：
文献类型：
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作者：
Gross,Golda;Alkadieri,Suha;Meir,Amilia;Itzhaki,Orit;Aharony-Tevet,Yarden;Yosef,ShaharBen;Zenab,Angi;Shbiro,Liat;Toren,Amos;Yardeni,Tal;Jacoby,Elad
CD 19 CAR-T细胞已导致难治性B细胞恶性肿瘤患者的持久缓解;然而，大多数患者最终会长期复发。已经报道了许多旨在改善当前产品的干预措施，其中一部分集中在与CAR-T细胞代谢状态的直接或间接联系上。我们评估了一项正在进行的临床试验的临床产品，该试验使用了来自急性淋巴细胞白血病患者的CD 19 - 28 z CAR-T细胞。导致完全缓解的CAR-T临床产品具有显著更高的线粒体功能（根据耗氧率），无论线粒体含量如何。接下来，我们将培养基的碳源从葡萄糖替换为半乳糖以影响细胞代谢。含半乳糖的培养基增加了CAR-T细胞中的线粒体活性，并改善了体外功效，而记忆特征没有任何一致的表型变化。最后，在基于半乳糖的无葡萄糖培养基中产生的CAR-T细胞导致线粒体活性增加。使用注射Nalm 6的小鼠的体内模型，与标准葡萄糖培养的CAR-T细胞相比，半乳糖引发的CAR-T细胞显着改善了无白血病存活率。我们的研究结果证明了线粒体代谢对CAR-T细胞功效的重要性，并提出了改善临床产品的翻译途径。
CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in in-vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using an in-vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.