Differential susceptibility and role for senescence in CART cells based on costimulatory domains
Abstract Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro m...
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2025-06-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02371-1 |
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| author | Ismail Can Elizabeth L. Siegler Olivia L. Sirpilla Claudia Manriquez-Roman Kun Yun Carli M. Stewart Jennifer M. Feigin Makena L. Rodriguez Omar L. Gutierrez-Ruiz Ekene J. Ogbodo Truc N. Huynh Brooke L. Kimball Long K. Mai Mehrdad Hefazi Lionel Kankeu Fonkoua Hong Xia Imene Hamaidi Berke Alkan Fatih Sezer H. Atakan Ekiz R. Leo Sakemura Saad S. Kenderian |
| author_facet | Ismail Can Elizabeth L. Siegler Olivia L. Sirpilla Claudia Manriquez-Roman Kun Yun Carli M. Stewart Jennifer M. Feigin Makena L. Rodriguez Omar L. Gutierrez-Ruiz Ekene J. Ogbodo Truc N. Huynh Brooke L. Kimball Long K. Mai Mehrdad Hefazi Lionel Kankeu Fonkoua Hong Xia Imene Hamaidi Berke Alkan Fatih Sezer H. Atakan Ekiz R. Leo Sakemura Saad S. Kenderian |
| author_sort | Ismail Can |
| collection | DOAJ |
| description | Abstract Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells. |
| format | Article |
| id | doaj-art-d129db6db3064e2b889cc304e06deaec |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-d129db6db3064e2b889cc304e06deaec2025-08-20T02:06:31ZengBMCMolecular Cancer1476-45982025-06-0124111610.1186/s12943-025-02371-1Differential susceptibility and role for senescence in CART cells based on costimulatory domainsIsmail Can0Elizabeth L. Siegler1Olivia L. Sirpilla2Claudia Manriquez-Roman3Kun Yun4Carli M. Stewart5Jennifer M. Feigin6Makena L. Rodriguez7Omar L. Gutierrez-Ruiz8Ekene J. Ogbodo9Truc N. Huynh10Brooke L. Kimball11Long K. Mai12Mehrdad Hefazi13Lionel Kankeu Fonkoua14Hong Xia15Imene Hamaidi16Berke Alkan17Fatih Sezer18H. Atakan Ekiz19R. Leo Sakemura20Saad S. Kenderian21T Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicCancer Biology, Mayo ClinicDepartment of Molecular Biology and Genetics, Izmir Institute of TechnologyDepartment of Molecular Biology and Genetics, Izmir Institute of TechnologyDepartment of Molecular Biology and Genetics, Izmir Institute of TechnologyT Cell Engineering, Mayo ClinicT Cell Engineering, Mayo ClinicAbstract Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells.https://doi.org/10.1186/s12943-025-02371-1Chimeric antigen receptor T cell therapySenescenceExhaustionMYCImmunotherapy |
| spellingShingle | Ismail Can Elizabeth L. Siegler Olivia L. Sirpilla Claudia Manriquez-Roman Kun Yun Carli M. Stewart Jennifer M. Feigin Makena L. Rodriguez Omar L. Gutierrez-Ruiz Ekene J. Ogbodo Truc N. Huynh Brooke L. Kimball Long K. Mai Mehrdad Hefazi Lionel Kankeu Fonkoua Hong Xia Imene Hamaidi Berke Alkan Fatih Sezer H. Atakan Ekiz R. Leo Sakemura Saad S. Kenderian Differential susceptibility and role for senescence in CART cells based on costimulatory domains Molecular Cancer Chimeric antigen receptor T cell therapy Senescence Exhaustion MYC Immunotherapy |
| title | Differential susceptibility and role for senescence in CART cells based on costimulatory domains |
| title_full | Differential susceptibility and role for senescence in CART cells based on costimulatory domains |
| title_fullStr | Differential susceptibility and role for senescence in CART cells based on costimulatory domains |
| title_full_unstemmed | Differential susceptibility and role for senescence in CART cells based on costimulatory domains |
| title_short | Differential susceptibility and role for senescence in CART cells based on costimulatory domains |
| title_sort | differential susceptibility and role for senescence in cart cells based on costimulatory domains |
| topic | Chimeric antigen receptor T cell therapy Senescence Exhaustion MYC Immunotherapy |
| url | https://doi.org/10.1186/s12943-025-02371-1 |
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