CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome.
CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome.
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DOI：
10.1172/jci150807
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发表时间：
2022-06-15
影响因子：
15.9
通讯作者：
Casucci, Monica
中科院分区：
文献类型：
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作者：
Arcangeli, Silvia;Bove, Camilla;Mezzanotte, Claudia;Camisa, Barbara;Falcone, Laura;Manfredi, Francesco;Bezzecchi, Eugenia;El Khoury, Rita;Norata, Rossana;Sanvito, Francesca;Ponzoni, Maurilio;Greco, Beatrice;Moresco, Marta Angiola;Carrabba, Matteo G.;Ciceri, Fabio;Bonini, Chiara;Bondanza, Attilio;Casucci, Monica
嵌合抗原受体 (CAR) T 细胞的扩增和持久性是实现完全缓解和防止复发的关键因素。这些特征是早期记忆 T 细胞的典型特征，可以通过优化的制造方案来高度丰富。在这里，我们研究了由预选的初始/干记忆 T 细胞 (TN/SCM) 生成的 CAR T 细胞产品与未选择的 T 细胞 (TBULK) 相比的功效和安全性。尽管体外效应信号降低，但限制 CAR TN/SCM 剂量在造血干细胞/前体细胞人源化小鼠中显示出优异的抗肿瘤活性和对抗白血病再攻击的独特能力，其特点是增加的扩增率和持久性以及改善的耗竭和记忆表型。最相关的是，CAR TN/SCM 被证明本质上不太容易诱发严重的细胞因子释放综合征，与所使用的共刺激内域无关。这种更安全的情况与较温和的 T 细胞激活有关，这会转化为单核细胞激活和细胞因子释放的减少。这些数据表明，与CAR TBULK相比，CAR TN/SCM具有更广泛的治疗指数。
Chimeric antigen receptor (CAR) T cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM), as compared with unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia rechallenge in hematopoietic stem/precursor cell–humanized mice, featuring increased expansion rates and persistence together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to inducing severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T cell activation, which translated into reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared with CAR TBULK.