Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors.
Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors.
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DOI：
10.3389/fonc.2020.574860
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发表时间：
2020
影响因子：
4.7
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Fan J;Das JK;Xiong X;Chen H;Song J
嵌合抗原受体（CAR）T细胞（CAR - T）疗法在血液系统恶性肿瘤中取得了巨大成功，但对实体瘤仅显示出有限的效果。主要障碍之一是源于体外激活/扩增的回输细胞持久性差以及回输后反复接触抗原。Bcl - xL已被证明在正常T细胞存活和功能以及基因工程细胞中发挥重要作用。在当前研究中，我们开发了一种逆转录病毒CAR构建体，其包含一个带有Bcl - xL基因的第二代靶向癌胚抗原（CEA）的CAR，并测试了抗CEA的CAR - T细胞免疫疗法用于结直肠癌的效果。在体外，抗CEA的CAR - T细胞能够摧毁表达CEA的肿瘤细胞并持续存活。在体内，在结直肠癌小鼠模型中，抗CEA的CAR - T细胞过继性回输显著增强了CAR - T细胞在肿瘤组织中聚集的能力，抑制了肿瘤生长，并提高了荷瘤小鼠的总体存活率。这些结果展示了一种新型CAR - T平台，该平台能够通过持久性基因的外源表达增加CAR - T细胞在实体瘤中的持久性。这些数据为增强实体瘤的CAR - T免疫疗法提供了一种潜在的新方法。
Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
DOI：
10.1073/pnas.1610544113
发表时间：
2016-11-29
影响因子：
11.1
作者：
Hurton, Lenka V.;Singh, Harjeet;Cooper, Laurence J. N.
通讯作者：
Cooper, Laurence J. N.
影响因子：
4.4
作者：
Burr, JS;Savage, NDL;Green, JM
通讯作者：
Green, JM
影响因子：
20.3
作者：
Newrzela, Sebastian;Cornils, Kerstin;von Laer, Dorothee
通讯作者：
von Laer, Dorothee
影响因子：
11.2
作者：
Lei, Fengyang;Zhao, Baohua;Song, Jianxun
通讯作者：
Song, Jianxun