Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model
Background Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequ...
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e008572.full |
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| author | Felipe Prosper Sandra Hervás-Stubbs Juan Jose Lasarte Noelia Casares Teresa Lozano Celia Martín-Otal Aritz Lasarte-Cia Flor Navarro Inés Sánchez-Moreno Marta Gorraiz Patricia Sarrión Juan Roberto Rodriguez-Madoz Jesús San Miguel Lorea Jordana |
| author_facet | Felipe Prosper Sandra Hervás-Stubbs Juan Jose Lasarte Noelia Casares Teresa Lozano Celia Martín-Otal Aritz Lasarte-Cia Flor Navarro Inés Sánchez-Moreno Marta Gorraiz Patricia Sarrión Juan Roberto Rodriguez-Madoz Jesús San Miguel Lorea Jordana |
| author_sort | Felipe Prosper |
| collection | DOAJ |
| description | Background Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.Methods We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.Results Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.Conclusion Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity. |
| format | Article |
| id | doaj-art-9476ec368d284e2c9962de6926e355ea |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9476ec368d284e2c9962de6926e355ea2025-08-20T03:15:57ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2023-008572Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse modelFelipe Prosper0Sandra Hervás-Stubbs1Juan Jose Lasarte2Noelia Casares3Teresa Lozano4Celia Martín-Otal5Aritz Lasarte-Cia6Flor Navarro7Inés Sánchez-Moreno8Marta Gorraiz9Patricia Sarrión10Juan Roberto Rodriguez-Madoz11Jesús San Miguel12Lorea Jordana13Hemato-Oncology Program, Centre for Applied Medical Research (CIMA), University of Navarra, IdiSNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainProgram of Immunology and Inmunoterapy, CIMA Universidad de Navarra, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainImmunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, SpainCancer Center Universidad de Navarra (CCUN), Pamplona, SpainCancer Center Universidad de Navarra (CCUN), Pamplona, SpainHemato-Oncology Program, Centre for Applied Medical Research (CIMA), University of Navarra, IdiSNA, Pamplona, SpainBackground Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.Methods We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.Results Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.Conclusion Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.https://jitc.bmj.com/content/12/7/e008572.full |
| spellingShingle | Felipe Prosper Sandra Hervás-Stubbs Juan Jose Lasarte Noelia Casares Teresa Lozano Celia Martín-Otal Aritz Lasarte-Cia Flor Navarro Inés Sánchez-Moreno Marta Gorraiz Patricia Sarrión Juan Roberto Rodriguez-Madoz Jesús San Miguel Lorea Jordana Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model Journal for ImmunoTherapy of Cancer |
| title | Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model |
| title_full | Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model |
| title_fullStr | Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model |
| title_full_unstemmed | Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model |
| title_short | Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model |
| title_sort | tethered il15 il15rα augments antitumor activity of cd19 car t cells but displays long term toxicity in an immunocompetent lymphoma mouse model |
| url | https://jitc.bmj.com/content/12/7/e008572.full |
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