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Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells t...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751546/ https://www.ncbi.nlm.nih.gov/pubmed/29298689 http://dx.doi.org/10.1186/s13045-017-0548-2 |
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author | Yu, Jiayi Wu, Xiaowen Yan, Junya Yu, Huan Xu, Longwen Chi, Zhihong Sheng, Xinan Si, Lu Cui, Chuanliang Dai, Jie Ma, Meng Xu, Tianxiao Kong, Yan Guo, Jun |
author_facet | Yu, Jiayi Wu, Xiaowen Yan, Junya Yu, Huan Xu, Longwen Chi, Zhihong Sheng, Xinan Si, Lu Cui, Chuanliang Dai, Jie Ma, Meng Xu, Tianxiao Kong, Yan Guo, Jun |
author_sort | Yu, Jiayi |
collection | PubMed |
description | BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research. METHODS: This study included tumor samples from 288 melanoma patients at the Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemical assays using antibodies against ganglioside GD2 were performed on formalin-fixed, paraffin-embedded specimens. The ability of ganglioside GD2 CAR-T cells to kill ganglioside GD2(+) melanoma cells was evaluated in vitro and in a patient-derived xenograft (PDX) model. RESULTS: Among the 288 samples, 49.3% of cases (142/288) demonstrated positive staining with ganglioside GD2. The median survival time in patients exhibiting ganglioside GD2 expression was significantly shorter than that in patients without ganglioside GD2 expression (31 vs. 47.1 months, P < 0.001). In the present study, CAR was constructed using a GD2-specific scFv (14.G2a), T cell receptor CD3ζ chain, and the CD137 (4-1BB) costimulatory motif. In addition, the GD2.BBζ CAR-T cells demonstrated specific lysis of ganglioside GD2-expressing melanoma cells in vitro. In two PDX models, mice that received intravenous or local intratumor injections of GD2.BBζ CAR-T cells experienced rapid tumor regression. CONCLUSIONS: These data demonstrate that the rate of GD2 expression in Chinese patients is 49.3%. GD2.BBζ CAR-T cells can both efficiently lyse melanoma in a GD2-specific manner and release Th1 cytokines in an antigen-dependent manner in vitro and in vivo. Anti-GD2/4-1BB CAR-T cells represent a clinically appealing treatment strategy for Chinese melanoma patients exhibiting GD2 expression and provide a basis for future studies of the clinical application of immunotherapy for melanoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-017-0548-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5751546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57515462018-01-05 Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients Yu, Jiayi Wu, Xiaowen Yan, Junya Yu, Huan Xu, Longwen Chi, Zhihong Sheng, Xinan Si, Lu Cui, Chuanliang Dai, Jie Ma, Meng Xu, Tianxiao Kong, Yan Guo, Jun J Hematol Oncol Research BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research. METHODS: This study included tumor samples from 288 melanoma patients at the Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemical assays using antibodies against ganglioside GD2 were performed on formalin-fixed, paraffin-embedded specimens. The ability of ganglioside GD2 CAR-T cells to kill ganglioside GD2(+) melanoma cells was evaluated in vitro and in a patient-derived xenograft (PDX) model. RESULTS: Among the 288 samples, 49.3% of cases (142/288) demonstrated positive staining with ganglioside GD2. The median survival time in patients exhibiting ganglioside GD2 expression was significantly shorter than that in patients without ganglioside GD2 expression (31 vs. 47.1 months, P < 0.001). In the present study, CAR was constructed using a GD2-specific scFv (14.G2a), T cell receptor CD3ζ chain, and the CD137 (4-1BB) costimulatory motif. In addition, the GD2.BBζ CAR-T cells demonstrated specific lysis of ganglioside GD2-expressing melanoma cells in vitro. In two PDX models, mice that received intravenous or local intratumor injections of GD2.BBζ CAR-T cells experienced rapid tumor regression. CONCLUSIONS: These data demonstrate that the rate of GD2 expression in Chinese patients is 49.3%. GD2.BBζ CAR-T cells can both efficiently lyse melanoma in a GD2-specific manner and release Th1 cytokines in an antigen-dependent manner in vitro and in vivo. Anti-GD2/4-1BB CAR-T cells represent a clinically appealing treatment strategy for Chinese melanoma patients exhibiting GD2 expression and provide a basis for future studies of the clinical application of immunotherapy for melanoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-017-0548-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-01-03 /pmc/articles/PMC5751546/ /pubmed/29298689 http://dx.doi.org/10.1186/s13045-017-0548-2 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Yu, Jiayi Wu, Xiaowen Yan, Junya Yu, Huan Xu, Longwen Chi, Zhihong Sheng, Xinan Si, Lu Cui, Chuanliang Dai, Jie Ma, Meng Xu, Tianxiao Kong, Yan Guo, Jun Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title | Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title_full | Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title_fullStr | Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title_full_unstemmed | Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title_short | Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients |
title_sort | anti-gd2/4-1bb chimeric antigen receptor t cell therapy for the treatment of chinese melanoma patients |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751546/ https://www.ncbi.nlm.nih.gov/pubmed/29298689 http://dx.doi.org/10.1186/s13045-017-0548-2 |
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