The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice
Chimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.01143/full |
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doaj-fce77531ae3a41a586cd38cedfb40a2e |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Panyuan Li Lingcong Yang Tong Li Shufang Bin Bohao Sun Yuting Huang Kaiyan Yang Daming Shan Haihua Gu Hongzhi Li |
| spellingShingle |
Panyuan Li Lingcong Yang Tong Li Shufang Bin Bohao Sun Yuting Huang Kaiyan Yang Daming Shan Haihua Gu Hongzhi Li The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice Frontiers in Oncology HER2 breast cancer chimeric antigen receptor (CAR)-T cells PD1 immunotherapy |
| author_facet |
Panyuan Li Lingcong Yang Tong Li Shufang Bin Bohao Sun Yuting Huang Kaiyan Yang Daming Shan Haihua Gu Hongzhi Li |
| author_sort |
Panyuan Li |
| title |
The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice |
| title_short |
The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice |
| title_full |
The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice |
| title_fullStr |
The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice |
| title_full_unstemmed |
The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent Mice |
| title_sort |
third generation anti-her2 chimeric antigen receptor mouse t cells alone or together with anti-pd1 antibody inhibits the growth of mouse breast tumor cells expressing her2 in vitro and in immune competent mice |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Oncology |
| issn |
2234-943X |
| publishDate |
2020-07-01 |
| description |
Chimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in immune competent mouse model. The PDL1-positive mouse mammary tumor cell line 4T1 engineered to express luciferase and human HER2 was used as the target cell line (4T1-Luc-HER2). Anti-HER2 CAR-T cells were generated by transducing mouse spleen T cells with recombinant lentiviruses. ELISA analysis showed that IL-2 and IFN-γ secretion was increased in CAR-T cells co-cultured with the target cells, and the secretion of these two cytokines was increased further with the addition of anti-PD1 antibody. Lactate dehydrogenase assay revealed that CAR-T cells displayed a potent cytotoxicity against the target cells, and the addition of anti-PD1 antibody further enhanced the cytotoxicity. At the effector: target ratio of 16:1, cytotoxicity was 39.8% with CAR-T cells alone, and increased to 49.5% with the addition of anti-PD1 antibody. In immune competent syngeneic mouse model, CAR-T cells were found to be present in tumor stroma, inhibited tumor growth and increased tumor apoptosis significantly. Addition of anti-PD1 antibody further enhanced these anti-tumor activities. Twenty-one days after treatment, tumor weight was reduced by 50.0% and 73.3% in CAR-T group and CAR-T plus anti-PD1 group compared with blank T group. Our results indicate that anti-PD1 antibody can greatly increase the efficacy of anti-HER2 CAR-T against HER2-positive solid tumors. |
| topic |
HER2 breast cancer chimeric antigen receptor (CAR)-T cells PD1 immunotherapy |
| url |
https://www.frontiersin.org/article/10.3389/fonc.2020.01143/full |
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| _version_ |
1724589236526514176 |
| spelling |
doaj-fce77531ae3a41a586cd38cedfb40a2e2020-11-25T03:27:09ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-07-011010.3389/fonc.2020.01143528631The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells Expressing HER2 in vitro and in Immune Competent MicePanyuan Li0Lingcong Yang1Tong Li2Shufang Bin3Bohao Sun4Yuting Huang5Kaiyan Yang6Daming Shan7Haihua Gu8Hongzhi Li9Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaThe Third People's Hospital of Dalian, Dalian, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaZhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, ChinaChimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in immune competent mouse model. The PDL1-positive mouse mammary tumor cell line 4T1 engineered to express luciferase and human HER2 was used as the target cell line (4T1-Luc-HER2). Anti-HER2 CAR-T cells were generated by transducing mouse spleen T cells with recombinant lentiviruses. ELISA analysis showed that IL-2 and IFN-γ secretion was increased in CAR-T cells co-cultured with the target cells, and the secretion of these two cytokines was increased further with the addition of anti-PD1 antibody. Lactate dehydrogenase assay revealed that CAR-T cells displayed a potent cytotoxicity against the target cells, and the addition of anti-PD1 antibody further enhanced the cytotoxicity. At the effector: target ratio of 16:1, cytotoxicity was 39.8% with CAR-T cells alone, and increased to 49.5% with the addition of anti-PD1 antibody. In immune competent syngeneic mouse model, CAR-T cells were found to be present in tumor stroma, inhibited tumor growth and increased tumor apoptosis significantly. Addition of anti-PD1 antibody further enhanced these anti-tumor activities. Twenty-one days after treatment, tumor weight was reduced by 50.0% and 73.3% in CAR-T group and CAR-T plus anti-PD1 group compared with blank T group. Our results indicate that anti-PD1 antibody can greatly increase the efficacy of anti-HER2 CAR-T against HER2-positive solid tumors.https://www.frontiersin.org/article/10.3389/fonc.2020.01143/fullHER2breast cancerchimeric antigen receptor (CAR)-T cellsPD1immunotherapy |