CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.
CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.
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DOI：
10.1136/jitc-2022-005878
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发表时间：
2023-01
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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迄今为止，用CD 19特异性嵌合抗原受体（CAR）重定向的T细胞在B细胞恶性肿瘤中取得了令人印象深刻的成功。然而，治疗失败是常见的，严重毒性的发生，如细胞因子释放综合征（CRS），仍然限制了这种方法的充分利用。因此，高度需要开发具有改善的治疗指数的细胞产品。在这个项目中，我们研究了CD 4和CD 8群体在CD 19 CAR-T细胞应答过程中如何合作，以及它们在CRS发展中的具体作用。为此，我们利用了用人类免疫系统（HuSGM 3）重建并移植B细胞急性淋巴细胞白血病细胞系NALM-6的免疫缺陷小鼠，这是一种允许彻底研究CD 19 CAR-T细胞产物的疗效和毒性特征的模型。CD 4 CAR-T细胞显示出上级增殖和活化潜力，这转化为对骨髓细胞的更强刺激，这是不良事件的主要触发因素。因此，HuSGM 3小鼠中的毒性评估将CD 4 CAR-T细胞鉴定为CRS发展的关键贡献者，揭示了当它们携带嵌入有4-1BB而不是CD 28的汽车时更安全的特征。通过比较差异共刺激的CD 4：CD 8 1：1 CAR-T细胞制剂，我们观察到CD 4细胞塑造了输注产品的整体扩增动力学，并且对于维持长期应答至关重要。有趣的是，CD4.BBz与CD8.28z CAR-T细胞的组合导致最低的毒性，而不影响抗肿瘤功效。总之，这些数据指出，改进的过继性T细胞疗法的合理设计应考虑CD 4 CAR-T细胞的生物学特征，这些特征对于维持长期应答至关重要，但也具有更高的毒性潜力。
To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded. In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products. CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy. Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.
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影响因子：
82.9
作者：
Deng Q;Han G;Puebla-Osorio N;Ma MCJ;Strati P;Chasen B;Dai E;Dang M;Jain N;Yang H;Wang Y;Zhang S;Wang R;Chen R;Showell J;Ghosh S;Patchva S;Zhang Q;Sun R;Hagemeister F;Fayad L;Samaniego F;Lee HC;Nastoupil LJ;Fowler N;Eric Davis R;Westin J;Neelapu SS;Wang L;Green MR
通讯作者：
Green MR
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
15.9
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
通讯作者：
Casucci, Monica
影响因子：
82.9
作者：
Gattinoni L;Speiser DE;Lichterfeld M;Bonini C
通讯作者：
Bonini C
影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.