Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome.
Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome.
复制标题
DOI：
10.1080/2162402x.2016.1211218
复制
发表时间：
2016
期刊：
影响因子：
7.2
通讯作者：
Shiku H
中科院分区：
文献类型：
--
作者：
Wang L;Ma N;Okamoto S;Amaishi Y;Sato E;Seo N;Mineno J;Takesako K;Kato T;Shiku H
癌胚抗原(CEA)是一种细胞表面抗原，在各种类型的癌细胞和健康组织中高度表达。它有可能成为嵌合抗原受体(CAR)修饰的T细胞治疗的靶点；然而，这种方法在靶上/肿瘤外效应方面的安全性还需要确定。为了在临床相关的模型中解决这个问题，我们使用了一个小鼠模型，在该模型中，表达CEA特异性CAR的T细胞被转移到生理性表达CEA作为自身抗原的CEA转基因(TG)肿瘤小鼠中。过继转移结合淋巴清除和清髓性预适应，在CEA-TG组有显著的肿瘤消退作用，但在野生型小鼠中没有。体重减轻与表达CEA的胃肠道的明显炎症无关，但与营养不良有关，反映为与厌食有关的全身细胞因子水平升高，这可以通过注射抗IL-6受体单抗来控制，而不会影响疗效。淋巴清除和清髓性预适应之间的明显关系，CAR-T细胞的疗效和非肿瘤毒性，需要开发CEA特异性CAR-T细胞，其信号域得到改善，需要不那么严格的预适应来实现其疗效。综上所述，这些结果提示CEA特异性CAR为基础的过继T细胞治疗对CEA阳性实体瘤患者可能是有效的。区分治疗效果和非肿瘤毒性之间的细微差别将涉及进一步修改CAR-T细胞和预适应方案。
Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA+ solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens.