Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor

被引：342

作者：

Ma, Leyuan ^{[1
,2
]}

Dichwalkar, Tanmay ^{[1
]}

Chang, Jason Y. H. ^{[1
]}

Cossette, Benjamin ^{[1
]}

Garafola, Daniel ^{[1
]}

Zhang, Angela Q. ^{[1
]}

Fichter, Michael ^{[1
]}

Wang, Chensu ^{[1
]}

Liang, Simon ^{[1
]}

Silva, Murillo ^{[1
]}

Kumari, Sudha ^{[1
]}

Mehta, Naveen K. ^{[1
,3
]}

Abraham, Wuhbet ^{[1
]}

Thai, Nikki ^{[1
]}

Li, Na ^{[1
]}

Wittrup, K. Dane ^{[1
,3
,4
]}

Irvine, Darrell J. ^{[1
,2
,3
,5
,6
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[3] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[5] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA

[6] MIT, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

SCIENCE | 2019年 / 365卷 / 6449期

关键词：

LYMPH; IMMUNOTHERAPY; CHALLENGES; THERAPY; MICE;

D O I：

10.1126/science.aav8692

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Chimeric antigen receptor-Tcell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.

引用

页码：162 / +

页数：39

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