Ramírez Fernández, ÁngelAguilar Sopeña, ÓscarDíez Alonso, LauraSegura Tudela, AlejandroDomínguez Alonso, CarmenRoda Navarro, PedroÁlvarez Vallina, LuisBlanco, Belén2025-05-142025-05-142022Ramírez-Fernández Á, Aguilar-Sopeña Ó, Díez-Alonso L, Segura-Tudela A, Domínguez-Alonso C, Roda-Navarro P, Álvarez-Vallina L, Blanco B. Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies. Oncoimmunology. 2022 Mar 23;11(1):2054106. doi: 10.1080/2162402X.2022.20541062162-402X10.1080/2162402X.2022.2054106https://hdl.handle.net/20.500.14352/120069Cancer immunotherapy strategies based on the endogenous secretion of T cell-redirecting bispecific antibodies by engineered T lymphocytes (STAb-T) are emerging as alternative or complementary approaches to those based on chimeric antigen receptors (CAR-T). The antitumor efficacy of bispecific anti-CD19 × anti-CD3 (CD19×CD3) T cell engager (BiTE)-secreting STAb-T cells has been demonstrated in several mouse models of B-cell acute leukemia. Here, we have investigated the spatial topology and downstream signaling of the artificial immunological synapses (IS) that are formed by CAR-T or STAb-T cells. Upon interaction with CD19-positive target cells, STAb-T cells form IS with structure and signal transduction, which more closely resemble those of physiological cognate IS, compared to IS formed by CAR-T cells expressing a second-generation CAR bearing the same CD19-single-chain variable fragment. Importantly, while CD3 is maintained at detectable levels on the surface of STAb-T cells, indicating sustained activation mediated by the secreted BiTE, the anti-CD19 CAR was rapidly downmodulated, which correlated with a more transient downstream signaling. Furthermore, CAR-T cells, but not STAb-T cells, provoke an acute loss of CD19 in target cells. Such differences might represent advantages of the STAb-T strategy over the CAR-T approach and should be carefully considered in order to develop more effective and safer treatments for hematological malignancies.engAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/journal article2162-4011https://doi.org/10.1080/2162402X.2022.205410635355682https://www.tandfonline.com/doi/full/10.1080/2162402X.2022.2054106#abstracthttps://pubmed.ncbi.nlm.nih.gov/35355682/open access612.017BiTECARCD19+ B cell malignanciesSTAbT cell-redirecting strategiesLeukemia relapseCiencias Biomédicas32 Ciencias Médicas