Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness
CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense...
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Elsevier
2024-09-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924000791 |
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| author | Wannakorn Khopanlert Pongsakorn Choochuen Kajornkiat Maneechai Nawaphat Jangphattananont Socheatraksmey Ung Shingo Okuno Peter Steinberger Judith Leitner Surasak Sangkhathat Pongtep Viboonjuntra Seitaro Terakura Jakrawadee Julamanee |
| author_facet | Wannakorn Khopanlert Pongsakorn Choochuen Kajornkiat Maneechai Nawaphat Jangphattananont Socheatraksmey Ung Shingo Okuno Peter Steinberger Judith Leitner Surasak Sangkhathat Pongtep Viboonjuntra Seitaro Terakura Jakrawadee Julamanee |
| author_sort | Wannakorn Khopanlert |
| collection | DOAJ |
| description | CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense tumoricidal activity and persistence. CD19.28.40z CAR-T cells promoted pNF-κB and pRelB downstream signaling while diminishing NFAT signaling upon antigen exposure. CD19.28.40z CAR-T cells demonstrated greater proliferation, which translated into effective anti-tumor cytotoxicity in long-term co-culture assay. Repetitive weekly antigen stimulation unveiled continuous CAR-T cell expansion while preserving central memory T cell subset and lower expression of exhaustion phenotypes. The intrinsic genes underlying CD19.28.40z CAR-T cell responses were compared with conventional CARs and demonstrated the up-regulated genes associated with T cell proliferation and memory as well as down-regulated genes related to apoptosis, exhaustion, and glycolysis pathway. Enrichment of genes toward T cell stemness, particularly SELL, IL-7r, TCF7, and KLF2, was observed. Effective and continuing anti-tumor cytotoxicity in vivo was exhibited in both B cell lymphoblastic leukemia and B cell non-Hodgkin lymphoma xenograft models while demonstrating persistent T cell memory signatures. The functional enhancement of CD37.28.40z CAR-T cell activities against CD37+ tumor cells was further validated. The modification of dual T/B cell signaling molecules remarkably maximized the efficacy of CAR-T cell therapy. |
| format | Article |
| id | doaj-art-76b990e4569a498a8459de9bdd366199 |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-76b990e4569a498a8459de9bdd3661992025-08-20T02:32:49ZengElsevierMolecular Therapy: Oncology2950-32992024-09-0132320083710.1016/j.omton.2024.200837Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemnessWannakorn Khopanlert0Pongsakorn Choochuen1Kajornkiat Maneechai2Nawaphat Jangphattananont3Socheatraksmey Ung4Shingo Okuno5Peter Steinberger6Judith Leitner7Surasak Sangkhathat8Pongtep Viboonjuntra9Seitaro Terakura10Jakrawadee Julamanee11Stem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, ThailandDepartment of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ThailandStem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, ThailandStem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ThailandStem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ThailandDepartment of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, JapanDivision for Immune Receptors and T Cell Activation, Institute of Immunology, Medical University of Vienna, Vienna 1090, AustriaDivision for Immune Receptors and T Cell Activation, Institute of Immunology, Medical University of Vienna, Vienna 1090, AustriaDepartment of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ThailandStem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ThailandDepartment of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, JapanStem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand; Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, Thailand; Corresponding author: Jakrawadee Julamanee, Stem Cell Laboratory, Hematology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense tumoricidal activity and persistence. CD19.28.40z CAR-T cells promoted pNF-κB and pRelB downstream signaling while diminishing NFAT signaling upon antigen exposure. CD19.28.40z CAR-T cells demonstrated greater proliferation, which translated into effective anti-tumor cytotoxicity in long-term co-culture assay. Repetitive weekly antigen stimulation unveiled continuous CAR-T cell expansion while preserving central memory T cell subset and lower expression of exhaustion phenotypes. The intrinsic genes underlying CD19.28.40z CAR-T cell responses were compared with conventional CARs and demonstrated the up-regulated genes associated with T cell proliferation and memory as well as down-regulated genes related to apoptosis, exhaustion, and glycolysis pathway. Enrichment of genes toward T cell stemness, particularly SELL, IL-7r, TCF7, and KLF2, was observed. Effective and continuing anti-tumor cytotoxicity in vivo was exhibited in both B cell lymphoblastic leukemia and B cell non-Hodgkin lymphoma xenograft models while demonstrating persistent T cell memory signatures. The functional enhancement of CD37.28.40z CAR-T cell activities against CD37+ tumor cells was further validated. The modification of dual T/B cell signaling molecules remarkably maximized the efficacy of CAR-T cell therapy.http://www.sciencedirect.com/science/article/pii/S2950329924000791MT: Regular IssueCD28/CD40co-stimulatory domainCD19CD37CAR-T cell |
| spellingShingle | Wannakorn Khopanlert Pongsakorn Choochuen Kajornkiat Maneechai Nawaphat Jangphattananont Socheatraksmey Ung Shingo Okuno Peter Steinberger Judith Leitner Surasak Sangkhathat Pongtep Viboonjuntra Seitaro Terakura Jakrawadee Julamanee Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness Molecular Therapy: Oncology MT: Regular Issue CD28/CD40 co-stimulatory domain CD19 CD37 CAR-T cell |
| title | Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness |
| title_full | Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness |
| title_fullStr | Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness |
| title_full_unstemmed | Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness |
| title_short | Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness |
| title_sort | co stimulation of cd28 cd40 signaling molecule potentiates car t cell efficacy and stemness |
| topic | MT: Regular Issue CD28/CD40 co-stimulatory domain CD19 CD37 CAR-T cell |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924000791 |
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