Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting.
Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting.
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DOI：
10.1016/j.ccell.2018.08.017
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发表时间：
2018-10-08
期刊：
影响因子：
50.3
通讯作者：
Karadimitris A
中科院分区：
文献类型：
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作者：
Rotolo A;Caputo VS;Holubova M;Baxan N;Dubois O;Chaudhry MS;Xiao X;Goudevenou K;Pitcher DS;Petevi K;Kachramanoglou C;Iles S;Naresh K;Maher J;Karadimitris A
嵌合抗原受体抗CD 19（CAR 19）-T细胞免疫疗法诱导的CD 19 + B细胞淋巴瘤临床缓解通常是短暂的。我们测试了CD 1d限制性不变自然杀伤T（iNKT）细胞的CAR 19工程化是否会导致增强的抗淋巴瘤活性。通过CD 1d和CAR 19-CD 19依赖性相互作用协同激活的CAR 19-iNKT细胞比CAR 19-T细胞在体外和体内对表达CD 1d的淋巴瘤更有效。CAR 19-iNKT细胞更强的体内抗淋巴瘤活性及其增强的根除脑淋巴瘤的能力支持了改善的无肿瘤生存期和总生存期。通过全反式视黄酸的CD 1D转录去抑制导致CAR 19-iNKT细胞对CD 19+慢性淋巴细胞白血病细胞的细胞毒性进一步增强。因此，iNKT细胞是淋巴瘤和其他可能表达CD 1d的癌症的基于CAR的免疫治疗的高效平台。CAR 19-iNKT细胞转导和临床规模扩增的定制方案CAR 19-iNKT比CAR 19-T细胞更高的可扩增性和CD 19 + CD 1d+靶点的杀伤CAR 19-iNKT细胞反应性增强通过αGalCer和ATRA延长CAR 19-iNKT细胞处理小鼠的存活和脑淋巴瘤根除Rotolo et al.显示抗CD 19嵌合抗原受体（CAR 19）工程化的CD 1d限制性不变NKT细胞（iNKT）比CAR 19-T细胞更有效地对抗表达CD 1d的淋巴瘤，包括脑中的淋巴瘤。CD 1d表达的去抑制进一步增强了CAR 19-iNKT的抗肿瘤功效。
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers. Bespoke protocol for CAR19-iNKT cell transduction and clinical scale expansion Higher CAR19-iNKT than CAR19-T cell expandability and killing of CD19+CD1d+ targets CAR19-iNKT cell reactivity potentiation by αGalCer and ATRA Prolonged survival and brain lymphoma eradication of CAR19-iNKT cell-treated mice Rotolo et al. show that anti-CD19 chimeric antigen receptor (CAR19)-engineered CD1d-restricted invariant NKT cells (iNKT) are more effective than CAR19-T cells against CD1d-expressing lymphomas, including those in the brain. De-repression of CD1d expression further enhances the anti-tumor efficacy of CAR19-iNKT.
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DOI：
10.4049/jimmunol.1003965
发表时间：
2011-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gordy LE;Bezbradica JS;Flyak AI;Spencer CT;Dunkle A;Sun J;Stanic AK;Boothby MR;He YW;Zhao Z;Van Kaer L;Joyce S
通讯作者：
Joyce S
影响因子：
20.3
作者：
Gorini, Francesca;Azzimonti, Laura;de Lalla, Claudia
通讯作者：
de Lalla, Claudia
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
5.1
作者：
Almasbak, H.;Walseng, E.;Kyte, J. A.
通讯作者：
Kyte, J. A.
DOI：
10.1084/jem.186.1.109
发表时间：
1997-07-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Exley M;Garcia J;Balk SP;Porcelli S
通讯作者：
Porcelli S