Synergistic activity of tafasitamab and metronomic chemotherapy on diffuse large B-cell lymphoma through inhibition of the AKT/mTOR signaling pathway

被引：0

作者：

Marta Banchi ^{[1
]}

Maria Christina Cox ^{[2
]}

Paola Orlandi ^{[3
]}

Arianna Bandini ^{[1
]}

Fabio Stefanelli ^{[3
]}

Silvio Chericoni ^{[4
]}

Guido Bocci ^{[4
]}

机构：

[1] Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Via Roma 55, Pisa

[2] Haematology Unit, Fondazione Policlinico Tor Vergata, Rome

[3] Department of Clinical and Experimental Medicine, University of Pisa, Pisa

[4] Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa

来源：

Scientific Reports | / 15卷 / 1期

关键词：

Diffuse large B-cell lymphoma; Etoposide; Metronomic chemotherapy; Tafasitamab; Vinorelbine;

D O I：

10.1038/s41598-025-95476-y

中图分类号：

学科分类号：

摘要：

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. © The Author(s) 2025.

引用

共 40 条

[1] Sehn L.H., Salles G., Diffuse Large B-Cell Lymphoma, Longo, D. L.) N. Engl. J. Med, 384, pp. 842-858, (2021)
[2] Roschewski M., Staudt L.M., Wilson W.H., Diffuse large B-cell lymphoma-treatment approaches in the molecular era, Nat. Rev. Clin. Oncol, 11, pp. 12-23, (2014)
[3] Awan F.T., Lapalombella R., Trotta R., Butchar J.P., Yu B., Benson D.M.J., Et al., CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody, Blood, 115, pp. 1204-1213, (2010)
[4] Horton H.M., Bernett M.J., Pong E., Peipp M., Karki S., Chu S.Y., Et al., Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia, Cancer Res, 68, pp. 8049-8057, (2008)
[5] Salles G., Duell J., Gonzalez Barca E., Tournilhac O., Jurczak W., Liberati A.M., Et al., Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): A multicentre, prospective, single-arm, phase 2 study, Lancet Oncol, 21, pp. 978-988, (2020)
[6] Carter R.H., Tuveson D.A., Park D.J., Rhee S.G., Fearon D.T., The CD19 complex of B lymphocytes. Activation of phospholipase C by a protein tyrosine kinase-dependent pathway that can be enhanced by the membrane IgM complex, J. Immunol, 147, pp. 3663-3671, (1991)
[7] Tedder T.F., CD19: a promising B cell target for rheumatoid arthritis, Nat. Rev. Rheumatol, 5, pp. 572-577, (2009)
[8] Mills D.M., Stolpa J.C., Cambier J.C., Modulation of MHC class II signal transduction by CD19, Adv. Exp. Med. Biol, 596, pp. 139-148, (2007)
[9] Bocci G., Kerbel R.S., Pharmacokinetics of metronomic chemotherapy: A neglected but crucial aspect, Nat. Rev. Clin Oncol, 13, pp. 659-673, (2016)
[10] Natale G., Bocci G., Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data, Cancer Lett. Elsevier Irel. Ltd, 432, pp. 28-37, (2018)

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