Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL
Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and...
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Format: | Article |
Language: | English |
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Elsevier
2021-12-01
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Series: | Molecular Therapy: Oncolytics |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052100125X |
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doaj-ed1b4f1d6e464db28f63138acac27495 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ming Sun Peipei Xu Enxiu Wang Min Zhou Tongpeng Xu Jing Wang Qian Wang Bo Wang Kaihua Lu Chen Wang Bing Chen |
spellingShingle |
Ming Sun Peipei Xu Enxiu Wang Min Zhou Tongpeng Xu Jing Wang Qian Wang Bo Wang Kaihua Lu Chen Wang Bing Chen Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL Molecular Therapy: Oncolytics r/r B-ALL CAR-T cells KIRS2/DAP12 signaling domain 4-1BB clinical trial |
author_facet |
Ming Sun Peipei Xu Enxiu Wang Min Zhou Tongpeng Xu Jing Wang Qian Wang Bo Wang Kaihua Lu Chen Wang Bing Chen |
author_sort |
Ming Sun |
title |
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL |
title_short |
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL |
title_full |
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL |
title_fullStr |
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL |
title_full_unstemmed |
Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL |
title_sort |
novel two-chain structure utilizing kirs2/dap12 domain improves the safety and efficacy of car-t cells in adults with r/r b-all |
publisher |
Elsevier |
series |
Molecular Therapy: Oncolytics |
issn |
2372-7705 |
publishDate |
2021-12-01 |
description |
Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted. |
topic |
r/r B-ALL CAR-T cells KIRS2/DAP12 signaling domain 4-1BB clinical trial |
url |
http://www.sciencedirect.com/science/article/pii/S237277052100125X |
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doaj-ed1b4f1d6e464db28f63138acac274952021-10-09T04:39:50ZengElsevierMolecular Therapy: Oncolytics2372-77052021-12-012396106Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALLMing Sun0Peipei Xu1Enxiu Wang2Min Zhou3Tongpeng Xu4Jing Wang5Qian Wang6Bo Wang7Kaihua Lu8Chen Wang9Bing Chen10Department of Oncology Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Suzhou, PR China; Nanjing CART Medical Technology Co., Ltd., Nanjing 210032, PR ChinaDepartment of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, PR China; Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nnajing 210008, PR ChinaNanjing CART Medical Technology Co., Ltd., Nanjing 210032, PR China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, PR China; Clinical Pathological Diagnosis & Research Center, Youjiang Medical University for Nationalities, Baise 533000, PR China; The Key Laboratory of Molecular Pathology (Hepatobiliary Diseases) of Guangxi, Baise 533000, PR ChinaDepartment of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, PR ChinaDepartment of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, PR ChinaJiangsu Runtian Pharmaceutical Chain Pharmacy Co., Ltd., Nanjing 210000, PR ChinaDepartment of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, PR ChinaDepartment of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, PR ChinaDepartment of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, PR China; Corresponding author: Kai-hua Lu, Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, PR China.Nanjing CART Medical Technology Co., Ltd., Nanjing 210032, PR China; Department of Research and Development, Nanjing Aide Institute of Immunotherapy, Nanjing 211808, PR China; Corresponding author: Chen Wang, Nanjing CART Medical Technology Co., Ltd, Nanjing 210032, PR China.Department of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, PR China; Corresponding author: Bing Chen, Department of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, PR China.Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted.http://www.sciencedirect.com/science/article/pii/S237277052100125Xr/r B-ALLCAR-T cellsKIRS2/DAP12 signaling domain4-1BBclinical trial |