Research publications

Found 3 publicacions matching the indicated search criteria.
Zanetti SR, Velasco-Hernandez T, Gutierrez-Agüera F, Díaz VM, Romecín PA, Roca-Ho H, Sánchez-Martínez D, Tirado N, Baroni ML, Petazzi P, Torres-Ruiz R, Molina O, Bataller A, Fuster JL, Ballerini P, Juan M, Jeremias I, Bueno C, Menéndez P

A novel and efficient tandem CD19- and CD22-directed CAR for B-cell ALL.

Mol Ther 31 Aug 2021, . Epub 31 Aug 2021
CD19-directed chimeric antigen receptor (CAR) T-cells have yielded impressive response rates in refractory/relapse B-cell acute lymphoblastic leukemia (B-ALL);however, most patients ultimately relapse due to poor CAR T-cell persistence or resistance of either CD19+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. Indeed, CD22-CAR T-cells have been clinically used in B-ALL patients, although relapse also occurs. Tcells engineered with a tandem CAR (Tan-CAR) containing in a single contruct both CD19 and CD22 scFvs, might be advantageus in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T-cells showed similar in vitro expansion than CD19-CAR T-cells with no increased of tonic signaling. CRISPR/Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples and patient-derived xenografts (PDXs). Strikingly, the robust anti-leukemic activity of the Tan-CAR was slightly more effective in controling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.
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Tejedor JR, Bueno C, Vinyoles M, Petazzi P, Agraz-Doblas A, Cobo I, Torres-Ruiz R, Bayón GF, Pérez RF, López-Tamargo S, Gutierrez-Agüera F, Santamarina-Ojeda P, Ramírez-Orellana M, Bardini M, Cazzaniga G, Ballerini P, Schneider P, Stam RW, Varela I, Fraga MF, Fernández AF, Menéndez P

Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B-cell acute lymphoblastic leukemia.

J Clin Invest 13 May 2021, . Epub 13 May 2021
B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicated by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged (MLLr) and non-MLLr iB-ALL leukemias uniformly treated according to Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression and gene co-expression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer-cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient-derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.
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Recasens-Zorzo C, Cardesa-Salzmann T, Petazzi P, Ros-Blanco L, Esteve-Arenys A, Clot G, Guerrero-Hernández M, Rodríguez V, Soldini D, Valera A, Moros A, Climent F, González-Barca E, Mercadal S, Arenillas L, Calvo X, Mate JL, Gutiérrez-García G, Casanova I, Mangues R, Sanjuan-Pla A, Bueno C, Menéndez P, Martínez A, Colomer D, Tejedor RE, Teixidó J, Campo E, López-Guillermo A, Borrell JI, Colomo L, Pérez-Galán P, Roué G

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.

Haematologica Apr 2019, 104 (4) 778-788. Epub 28 Jun 2018
Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.
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