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2 results on '"Mauro Lorenzo-Mohamed"'

1. Tinostamustine (EDO-S101), an Alkylating Deacetylase Inhibitor, Enhances the Efficacy of Daratumumab in Multiple Myeloma by Upregulation of CD38 and NKG2D Ligands

Author

Andrea Díaz-Tejedor, Javier Rodríguez-Ubreva, Laura Ciudad, Mauro Lorenzo-Mohamed, Marta González-Rodríguez, Bárbara Castellanos, Janet Sotolongo-Ravelo, Laura San-Segundo, Luis A. Corchete, Lorena González-Méndez, Montserrat Martín-Sánchez, María-Victoria Mateos, Enrique M. Ocio, Mercedes Garayoa, and Teresa Paíno

Subjects
multiple myeloma, daratumumab, tinostamustine, immunotherapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients’ samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs.

Published
2024
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2. Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Author

Mercedes Garayoa, Andrea Díaz-Tejedor, Ramón García-Sanz, Noemi Puig, Teresa Paíno, Mauro Lorenzo-Mohamed, Maria-Victoria Mateos, Junta de Castilla y León, European Commission, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, and Fundación Ramón Areces

Subjects
0301 basic medicine, Cancer Research, medicine.drug_class, medicine.medical_treatment, Review, Monoclonal antibody, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Immune system, Multiple myeloma, medicine, Cytotoxic T cell, Secretion, immunosuppression, Effector, business.industry, immune stimulating drugs, Immunosuppression, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, multiple myeloma, immune system, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, Monoclonal antibodies, monoclonal antibodies, Immune stimulating drugs, business
Abstract

© 2021 by the authors., Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments., A.D.-T was supported by a fellowship from the Regional Education Council of Castilla y Léon co-financed by the European Social Fund; T.P. is supported by a grant from Asociación Española Contra el Cáncer (AECC) (INVES18043PAÍN). This study was funded by the Instituto de Salud Carlos III and co-financed by FEDER (PI18/01600 and PI19/01384); by the AECC (Proyectos Estratégicos: PROYE20047GUTI); by Fundación Ramón Areces (FRA16/003); and by the Gerencia Regional de Salud, Junta de Castilla y León grants (GRS 2066/A/19).

Published
2021

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