WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7150
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Article Citation - WoS: 1Citation - Scopus: 1Differential Susceptibility and Role for Senescence in Cart Cells Based on Costimulatory Domains(BMC, 2025) Can, Ismail; Siegler, Elizabeth L.; Sirpilla, Olivia L.; Manriquez-Roman, Claudia; Yun, Kun; Stewart, Carli M.; Kenderian, Saad S.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-CD3 zeta (BB zeta) or CD28-CD3 zeta (28 zeta), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BB zeta. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BB zeta activity but improved 28 zeta 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 BB zeta but with improved clinical outcomes in 28 zeta treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells.Conference Object Citation - WoS: 1Differential Susceptibility To Senescence in Cart Cells Based on Co-Stimulatory Signaling(American Society of Hematology, 2022) Can, İsmail; Sakemura, Reona Leo; Manriquez-Roman, Claudia; Sirpilla, Olivia; Stewart, Carli M.; Yun, Kun; Cox, Michelle J.; Ekiz, AtakanCD19-directed chimeric antigen receptor (CART19) cells have emerged as a potentially curative immunotherapy in a subset of patients with hematological malignancies. While initial responses are impressive, the majority of responsive patients relapse within a year. Recent studies suggest that CART cells are susceptible to states of dysfunction. We aimed to study the development of T cell senescence in CART cells using similar constructs to the FDA-approved therapies, CART19-BBζ and CART19-28ζ, to determine the impact of co-stimulatory domains on CART cell senescence. We developed an in vitro model for repeated CART cell activation followed by rest to study the development of senescence and its impact on effector T cell functions. We examined CART cell immunophenotype, cell cycle regulators, and transcriptomic profile on days 0 (T cell), D8 (standard CART cell), 15 (after one activation cycle) and 22 (after two activation cycles).