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01.12.2017 | Rapid communication | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2017
Autoren:
Le Qin, Yunxin Lai, Ruocong Zhao, Xinru Wei, Jianyu Weng, Peilong Lai, Baiheng Li, Simiao Lin, Suna Wang, Qiting Wu, Qiubin Liang, Yangqiu Li, Xuchao Zhang, Yilong Wu, Pentao Liu, Yao Yao, Duanqing Pei, Xin Du, Peng Li
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-017-0437-8) contains supplementary material, which is available to authorized users.

Abstract

Background

Multiple iterations of chimeric antigen receptors (CARs) have been developed, mainly focusing on intracellular signaling modules. However, the effect of non-signaling extracellular modules on the expansion and therapeutic efficacy of CARs remains largely undefined.

Methods

We generated two versions of CAR vectors, with or without a hinge domain, targeting CD19, mesothelin, PSCA, MUC1, and HER2, respectively. Then, we systematically compared the effect of the hinge domains on the growth kinetics, cytokine production, and cytotoxicity of CAR T cells in vitro and in vivo.

Results

During in vitro culture period, the percentages and absolute numbers of T cells expressing the CARs containing a hinge domain continuously increased, mainly through the promotion of CD4+ CAR T cell expansion, regardless of the single-chain variable fragment (scFv). In vitro migration assay showed that the hinges enhanced CAR T cells migratory capacity. The T cells expressing anti-CD19 CARs with or without a hinge had similar antitumor capacities in vivo, whereas the T cells expressing anti-mesothelin CARs containing a hinge domain showed enhanced antitumor activities.

Conclusions

Hence, our results demonstrate that a hinge contributes to CAR T cell expansion and is capable of increasing the antitumor efficacy of some specific CAR T cells. Our results suggest potential novel strategies in CAR vector design.

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Zusatzmaterial
Additional file 1: Figure S1. Hinge incorporation can promote the expansion of CAR T cells. Flow cytometric analysis of the percentage of 19.28z, 19-H.28z T cells, Meso.28z, Meso-H.28z T cells, PSCA.28z, PSCA-H.28z T cells, and GFP control T cells from day 6 to 15 during the in vitro culture period. The data are representative of independent experiments verified with cells from over three individual healthy human donors. (JPG 2876 kb)
13045_2017_437_MOESM1_ESM.jpg
Additional file 2: Figure S2. Hinge incorporation promotes CD4+ anti-CD19 CAR T cell expansion. Flow cytometric analysis of the percentage of CD4+ and CD8+ GFP T, 19.28z T, and 19-H.28z T during the in vitro culture period. The data are representative of independent experiments verified with cells from over three individual healthy human donors. (JPG 2320 kb)
13045_2017_437_MOESM2_ESM.jpg
Additional file 3: Figure S3. Percentages of CD4+ and CD8+ CAR T cells without a hinge domain both tended to be stable throughout the in vitro culture period. Flow cytometric analysis of the percentage of CD4+ and CD8+ (A) 19.28z T, (B) Meso.28z T, (C) PSCA.28z T, (D) HER2.28z T, and (E) GFP control T cells during the in vitro culture period. The data are representative of independent experiments verified with cells from over three individual healthy human donors. (JPG 924 kb)
13045_2017_437_MOESM3_ESM.jpg
Literatur
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