RESUMEN
CD70 is expressed in up to 80% of nasopharyngeal carcinoma (NPC) cases. Cusatuzumab is a humanized anti-CD70 monoclonal antibody, with dual action mechanisms: induction of cytotoxicity against CD70+ tumor cells and reduction in CD70-CD27 signaling mediated immune evasion. The aim of this study was to assess the safety, pharmacokinetic profile, immunogenicity, pharmacodynamic profile, and preliminary activity of cusatuzumab in advanced NPC. Eleven patients were enrolled: one patient was assigned to arm A (adjuvant cusatuzumab monotherapy after curative chemoradiation), nine patients to arm B (cusatuzumab monotherapy; noncurative setting), and one patient to arm C (cusatuzumab + chemotherapy; noncurative setting); irrespective of tumoral CD70 expression. Both patients in arms A and C completed the study. All patients in arm B discontinued at an early stage. Five patients experienced grade greater than or equal to 3 nondrug related treatment-emergent adverse events, most commonly fatigue and pneumonia (18%). An infusion-related reaction was observed in two of 11 patients. Laboratory results showed no trend over time. Seven patients were eligible for response evaluation. No objective response to cusatuzumab was observed with stable disease being the best response. The current study indicates that the safety profile of cusatuzumab (with or without concurrent chemotherapy) is manageable in patients with advanced NPC, which is consistent with known safety profile. Limited activity of cusatuzumab in advanced NPC was observed. Combination therapies of cusatuzumab and other types of therapy should be explored for the improvement of activity in NPC and other CD70-expressing malignancies.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Ligando CD27 , Factores Inmunológicos/uso terapéutico , Carcinoma Nasofaríngeo/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/farmacología , Antineoplásicos/uso terapéutico , Ligando CD27/efectos de los fármacos , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/patología , Adulto JovenRESUMEN
INTRODUCTION: CD70 and CD27 constitute a ligand-receptor pair of the TNF ligand and receptor family which is of major importance for T-cell costimulation. In healthy individuals CD70 expression is restricted to activated T-cells, certain subsets of immune cells and to epithelial cells of the thymic medulla. CD27 is expressed by naïve and memory T-cells and certain types of immune cells. Strikingly, CD70 is also often highly expressed on T- and B-cell lymphomas and on a considerable fraction of solid tumors. AREAS COVERED: Based on a brief description of the signaling mechanisms and immune regulatory activities of CD70 and CD27, this review is focused on strategies and concepts that exploit the function and expression pattern of these molecules for therapeutic purposes. EXPERT OPINION: Therapeutic strategies have been developed that either aim to trigger or inhibit CD27 activity or solely use CD70 as a tumor marker. Some of these strategies are currently under consideration in clinical trials and have shown a good safety profile. The identification of biomarkers and stratification concepts is now important to ensure that a chosen CD70/CD27 targeting strategy fits optimally to the dominant function(s) of CD70 and CD27 in the corresponding individual case.
Asunto(s)
Ligando CD27/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/efectos de los fármacos , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Ligando CD27/inmunología , Humanos , Terapia Molecular Dirigida , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease involving multiple organs and characterized by overproduction of autoantibodies and T and B cell abnormalities. The treatment for SLE has been restricted to immunosuppressants and corticosteroids. Mycophenolate mofetil (MMF), as a relatively new immunosuppressant, is now widely used in the treatment of SLE patients, particularly those with nephritis. However, it is unclear whether mycophenolic acid (MPA) could modulate the reported disorders of epigenetic status in CD4(+)T cells from SLE patients. In this study, we demonstrated that MPA can upregulate the histone H3/H4 global acetylation status by regulating HATs and HDACs in lupus CD4(+)T cells. Furthermore, we found that MPA also affected the histone H4 acetylation and histone H3K4 tri-methylation levels in CD40L promoter region that inhibited the expression of CD40L. These findings indicate the potential epigenetic mechanism of therapeutic effects of MPA in SLE.