Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway
Abstract Tafasitamab is a novel humanized anti-CD19 monoclonal antibody, designed for the treatment of B-cell malignancies. Our study aims to enhance the direct, non-immune-mediated, activity of tafasitamab (TAFA) with the combination of metronomic chemotherapy (mCHEMO), including vinorelbine (mVNR)...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-95476-y |
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| author | Marta Banchi Maria Christina Cox Paola Orlandi Arianna Bandini Fabio Stefanelli Silvio Chericoni Guido Bocci |
| author_facet | Marta Banchi Maria Christina Cox Paola Orlandi Arianna Bandini Fabio Stefanelli Silvio Chericoni Guido Bocci |
| author_sort | Marta Banchi |
| collection | DOAJ |
| description | Abstract Tafasitamab is a novel humanized anti-CD19 monoclonal antibody, designed for the treatment of B-cell malignancies. Our study aims to enhance the direct, non-immune-mediated, activity of tafasitamab (TAFA) with the combination of metronomic chemotherapy (mCHEMO), including vinorelbine (mVNR) and etoposide (mETO), in preclinical models of diffuse large B-cell lymphoma (DLBCL). In vitro, the 144 h exposure of thrice-weekly mVNR, daily mETO, and single-dose TAFA significantly inhibited the viability of human CD19+ DLBCL cell lines (i.e., Toledo, OCI-LY3, and SU-DHL10) in a concentration-dependent manner. In all cell lines, the concomitant treatment with TAFA and mVNR or mETO showed a marked synergism, except for TAFA + mETO on SU-DHL10 cells. The TAFA + mCHEMO treatments promoted apoptosis, and the TAFA + mVNR combination significantly inhibited, already after 24 h, the phosphorylation of GSK3α/β, mTOR, p70S6K, RPS6, and TSC2 proteins in DLBCL cells. TAFA significantly increased the VNR and ETO intracellular concentrations in all DLBCL cells after 24 h, except for ETO levels in SU-DHL10. The TAFA + mCHEMO treatment strongly reduced the ABCB1, ABCG2, and c-MYC gene expression in SU-DHL10 cells. In vivo, the TAFA + mVNR combination was well tolerated, significantly reduced the volumes of subcutaneous DLBCL masses, and increased the overall survival of mice affected by systemic DLBCL. We report additional mechanisms to enhance the direct activity of TAFA with mCHEMO synergistically in DLBCL cells in vitro and in vivo, suggesting the use of this combination schedule into future clinical trials. |
| format | Article |
| id | doaj-art-92650cbf24564cd5aab6bf089765855b |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-92650cbf24564cd5aab6bf089765855b2025-08-20T03:07:41ZengNature PortfolioScientific Reports2045-23222025-04-0115111410.1038/s41598-025-95476-ySynergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathwayMarta Banchi0Maria Christina Cox1Paola Orlandi2Arianna Bandini3Fabio Stefanelli4Silvio Chericoni5Guido Bocci6Department of Translational Research and of New Surgical and Medical Technologies, University of PisaHaematology Unit, Fondazione Policlinico Tor VergataDepartment of Clinical and Experimental Medicine, University of PisaDepartment of Translational Research and of New Surgical and Medical Technologies, University of PisaDepartment of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of PisaDepartment of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of PisaDepartment of Translational Research and of New Surgical and Medical Technologies, University of PisaAbstract Tafasitamab is a novel humanized anti-CD19 monoclonal antibody, designed for the treatment of B-cell malignancies. Our study aims to enhance the direct, non-immune-mediated, activity of tafasitamab (TAFA) with the combination of metronomic chemotherapy (mCHEMO), including vinorelbine (mVNR) and etoposide (mETO), in preclinical models of diffuse large B-cell lymphoma (DLBCL). In vitro, the 144 h exposure of thrice-weekly mVNR, daily mETO, and single-dose TAFA significantly inhibited the viability of human CD19+ DLBCL cell lines (i.e., Toledo, OCI-LY3, and SU-DHL10) in a concentration-dependent manner. In all cell lines, the concomitant treatment with TAFA and mVNR or mETO showed a marked synergism, except for TAFA + mETO on SU-DHL10 cells. The TAFA + mCHEMO treatments promoted apoptosis, and the TAFA + mVNR combination significantly inhibited, already after 24 h, the phosphorylation of GSK3α/β, mTOR, p70S6K, RPS6, and TSC2 proteins in DLBCL cells. TAFA significantly increased the VNR and ETO intracellular concentrations in all DLBCL cells after 24 h, except for ETO levels in SU-DHL10. The TAFA + mCHEMO treatment strongly reduced the ABCB1, ABCG2, and c-MYC gene expression in SU-DHL10 cells. In vivo, the TAFA + mVNR combination was well tolerated, significantly reduced the volumes of subcutaneous DLBCL masses, and increased the overall survival of mice affected by systemic DLBCL. We report additional mechanisms to enhance the direct activity of TAFA with mCHEMO synergistically in DLBCL cells in vitro and in vivo, suggesting the use of this combination schedule into future clinical trials.https://doi.org/10.1038/s41598-025-95476-yDiffuse large B-cell lymphomaMetronomic chemotherapyVinorelbineEtoposideTafasitamab |
| spellingShingle | Marta Banchi Maria Christina Cox Paola Orlandi Arianna Bandini Fabio Stefanelli Silvio Chericoni Guido Bocci Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway Scientific Reports Diffuse large B-cell lymphoma Metronomic chemotherapy Vinorelbine Etoposide Tafasitamab |
| title | Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway |
| title_full | Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway |
| title_fullStr | Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway |
| title_full_unstemmed | Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway |
| title_short | Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway |
| title_sort | synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large b cell lymphoma through inhibition of the akt mtor signaling pathway |
| topic | Diffuse large B-cell lymphoma Metronomic chemotherapy Vinorelbine Etoposide Tafasitamab |
| url | https://doi.org/10.1038/s41598-025-95476-y |
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