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

• Published in: International journal of molecular sciences Vol. 25; no. 9; p. 4718
• Main Authors: Díaz-Tejedor, Andrea, Rodríguez-Ubreva, Javier, Ciudad, Laura, Lorenzo-Mohamed, Mauro, González-Rodríguez, Marta, Castellanos, Bárbara, Sotolongo-Ravelo, Janet, San-Segundo, Laura, Corchete, Luis A, González-Méndez, Lorena, Martín-Sánchez, Montserrat, Mateos, María-Victoria, Ocio, Enrique M, Garayoa, Mercedes, Paíno, Teresa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.05.2024
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - metabolism; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antigens; Bone marrow; Cell Line, Tumor; Cells; Cytotoxicity; daratumumab; Drug Synergism; Epigenetics; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Immunotherapy; Killer cells; Leukemia; Ligands; Membrane Glycoproteins - metabolism; Mice; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Plasma; Statistical significance; tinostamustine; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Nigeria; Spain; multiple myeloma; tinostamustine; daratumumab; immunotherapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25094718

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.