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We thank R. Vilella for generating and providing the A3B1 antibody, F. Sanchez-Madrid for reagents, and the staff of the fluorescence microscopy facility of the Complutense University of Madrid for assistance with the confocal microscopy. We thank CRIS Cancer Foundation, CERCA/Generalitat de Catalunya, and Fundacio Josep Carreras-Obra Social la Caixa for core support. Financial support for this work was obtained from the European Research Council (CoG-2014-646903, PoC-2018-811220, to P. Menendez); the Spanish Ministry of Science and Innovation (PID2019-105623RB-I00, to M.L. Toribio; SAF201675656-P and RTC-2017-5944-1, to P. Roda-Navarro; SAF-2019-108160-R, to P. Menendez; and SAF2017-89437-P, PID2020-117323RB-100, and PDC2021121711-100, to L. Alvarez-Vallina), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII, PI20/01030, to B. Blanco; PI20/00822 to C. Bueno; PI16/00357 and PI19/00132 to L. Sanz; PICI14/122, PI13/676, PIE13/33, and PI18/775, to M. Juan; DTS20/00089, to L. Alvarez-Vallina), partially supported by the ERDF; the Obra Social La Caixa (LCF/PR/HR19/52160011, to P. Menendez), CatSalut, Fundacio La Caixa (CP042702, to M. Juan); the Spanish Association Against Cancer (AECC CICPF18030TORI, to M.L. Toribio; AECC 19084, to L. Alvarez-Vallina); Fundacion Uno Entre Cien Mil, and Fundacion Ramon Areces to M.L. Toribio; and the CRIS Cancer Foundation (FCRIS-IFI-2018 and FCRIS-IFI-2020, to L. Alvarez-Vallina). ISCIII-RICORS is supported within the Next Generation EU program (Plan de Recuperacion, Transformaci~on y Resiliencia). S. Guedan has received funding from the Spanish Ministry of Science and Innovation under a Ramon y Cajal grant (RYC2018-024442-I). A. Tapia-Galisteo was supported by predoctoral fellowship from Comunidad Aut~onoma de Madrid (PEJD-2018-PRE/BMD-8314). L. Diez-Alonso was supported by a Rio Hortega fellowship from the ISCIII (CM20/00004). L. RubioP~erez was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. C. Dominguez-Alonso was supported by a predoctoral fellowship from the Spanish Ministry of Science and Innovation (PRE2018-083445). M. Neves was supported by a grant from Portuguese Foundation for Science and Technology (SFRH/BD/136574/2018).

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Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers

Publicat a:Cancer Immunology Research. 10 (4): 498-511 - 2022-04-01 10(4), DOI: 10.1158/2326-6066.cir-21-0853

Autors: Blanco, Belen; Ramirez-Fernandez, Angel; Bueno, Clara; Argemi-Muntadas, Lidia; Fuentes, Patricia; Aguilar-Sopena, Oscar; Gutierrez-Aguera, Francisco; Zanetti, Samanta Romina; Tapia-Galisteo, Antonio; Diez-Alonso, Laura; Segura-Tudela, Alejandro; Castella, Maria; Marzal, Berta; Betriu, Sergi; Harwood, Seandean L; Compte, Marta; Lykkemark, Simon; Erce-Llamazares, Ainhoa; Rubio-Perez, Laura; Jimenez-Reinoso, Anais; Dominguez-Alonso, Carmen; Neves, Maria; Morales, Pablo; Paz-Artal, Estela; Guedan, Sonia; Sanz, Laura; Toribio, Maria L; Roda-Navarro, Pedro; Juan, Manel; Menendez, Pablo; Alvarez-Vallina, Luis

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Chimeric antigen receptor (CAR)-modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CAR-T19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti-CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.©2022 The Authors; Published by the American Association for Cancer Research.

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