1995;147:1152\1160. 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Currently, a multitude of immunotherapies are studied for their possible use in various solid carcinomas. Extensive research of the tumor microenvironment is done to determine possible immunological key mechanisms, which are related to tumor growth and progression. In this matter, chronic tumoral CD70 expression enhances proliferation of inhibitory regulatory T\cells within the tumor microenvironment via activation of the CD70/CD27 axis. Upregulated CD70 expression, reported in high incidence in Epstein\Barr virus\related nasopharyngeal carcinoma (NPC), is considered a possible key pathophysiologic mechanism of NPC carcinogenesis and has emerged as a potential target. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated if cusatuzumab, an anti\CD70 antibody, administered in patients with NPC at 5?mg/kg every 3?weeks intravenously, is safe and shows any clinical activity. Next, several biomarkers related to NPC (Epstein\Barr virus DNA copy numbers) or the tumor microenvironment (soluble CD27) were assessed for any possible indication for clinical activity of cusatuzumab. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? A manageable safety profile was observed, comparable to previously reported grade greater than or equal to three treatment\emerging adverse events for cusatuzumab. No response was observed with stable disease as best overall response, and median progression\free survival was 11.6?weeks. No changes in biomarkers were observed, which may indicate the beneficial effect of cusatuzumab given 5?mg/kg every 3?weeks intravenously. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY Rabbit Polyclonal to HMGB1 OR TRANSLATIONAL SCIENCE? In light of these results, activity of cusatuzumab should be evaluated in combination with other therapies, such as chemotherapy or an anti\PD\(L)1 agent. This should be done especially in Epstein\Barr virus\induced malignancies with confirmed high tumoral CD70 expression as this might increase the chance of clinical activity of cusatuzumab. Moreover, as a manageable safety profile was observed for the administration of cusatuzumab at 5?mg/kg every 3?weeks intravenously, it Methylprednisolone hemisuccinate should be considered to evaluate activity of cusatuzumab doses higher than 5?mg/kg every 3?weeks. This as recent data in other malignancies shows an acceptable safety profile at a dose as high as 20?mg/kg every 2?weeks. INTRODUCTION Nasopharyngeal carcinoma (NPC) arises from the epithelial lining of the nasopharynx, which is the narrow passage behind the nasal cavity. It represents up to 95% of malignancies originating from the nasopharynx. The treatment of choice for early stage NPC is single\modality radiotherapy. However, most patients are diagnosed with locally advanced stage disease and thus, require a more aggressive approach, based on concurrent chemoradiotherapy, combined with neoadjuvant or adjuvant (platinum\based) chemotherapy. In recurrent or metastatic disease, chemotherapy\based systemic therapy is the most common strategy, although with limited success. 1 Advances in the treatment of NPC have been hampered by its relatively low prevalence. Comparative studies indicate that such advances are unlikely to arise from variations in radiochemotherapy regimens. 2 , 3 On the other hand, immune checkpoint Methylprednisolone hemisuccinate inhibition with anti\programmed cell death protein\1 (PD\1) agents for metastatic NPC is being tested in phase I and II trials, with acceptable safety profiles and promising response rates up to 34%. 4 , 5 , 6 Methylprednisolone hemisuccinate Currently, the molecular underpinnings of Epstein\Barr virus (EBV)\induced malignancies, which are correlated to poor prognosis, 7 are being unraveled and upregulated CD70 expression Methylprednisolone hemisuccinate was reported as a potential target in NPC. 8 CD70 is a member of the tumor necrosis factor ligand family. In physiological conditions, CD70 is upregulated on activated T\cells, B\cells, and dendritic cells, serving as a unique ligand of CD27, which is Methylprednisolone hemisuccinate expressed on early thymocytes, naive T\cells, and activated B\cells. The CD70/CD27 costimulatory.