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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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Castella Pericas, ManelAuthorCastella MAuthorMarzal BAuthorBetriu SAuthorGuedan SAuthorJuan MAuthor

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Article

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

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

Authors: 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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Abstract

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.

Keywords

antibodyefficacyin-vivoinductioninhibitionlymphomamoleculessynapsestumor-growthAnimal cellAnimal experimentAnimal modelAnimal tissueAnimalsAntibody productionAntigens, cd19Antineoplastic activityArticleCancer growthCd19 antigenCd3 antigenCell contactChildChimeric antigen receptorChimeric antigen receptor t-cell immunotherapyChronic patientClinical articleComparative studyControlled studyCytolysisCytotoxicityCytotoxicity assayEnzymatic degradationGene transferHumanHuman cellHuman tissueHumansImmune responseImmunological synapseImmunotherapy, adoptiveIn vitro studyIn vivo studyInternalization (cell)LeukemiaLeukemia cellLeukemia relapseLysosomeMiceMolecular weightMouseMouse modelNalm-6 cell lineNonhumanPreschool childProtein expressionProtein targetingRecurrenceT lymphocyteT-lymphocytesTarget cellTumor escapeTumor xenograft

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancer Immunology Research due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 19/161, thus managing to position itself as a Q1 (Primer Cuartil), in the category Immunology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.53. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.52 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 7.62 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-28, the following number of citations:

  • WoS: 16
  • Scopus: 19
  • Europe PMC: 6
  • OpenCitations: 18

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-28:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 58.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 56 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 9.15.
  • The number of mentions on the social network X (formerly Twitter): 13 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Denmark.