Denosumab In Ebv Nasopharyngeal Carcinoma As A Model For RankMediated Immunologic Modulation Of Virus-Related Tumours

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Approximately 15-20% of the cancers recognize infectious agents as causal factors. Epstein Barr Virus (EBV) is considered carcinogenic to humans for haematological and solid neoplasms such as nasopharyngeal carcinoma (NPC). Oncogenic mechanisms linking EBV with NPC need to be better delineated. Howe...

Approximately 15-20% of the cancers recognize infectious agents as causal factors. Epstein Barr Virus (EBV) is considered carcinogenic to humans for haematological and solid neoplasms such as nasopharyngeal carcinoma (NPC). Oncogenic mechanisms linking EBV with NPC need to be better delineated. However, the well-defined patterns of EBV cancer cells infection, together with its encoded regulated genes in tumours offers an option for immunological therapeutic strategies. Distant metastases, especially of the bone, occurs in up to half of patients with NPC. This underlines the importance of improving systemic disease control. Intravenous bisphosphonates (BP) are effective treatments for skeletal-related events (SRE) in patients with bone metastases. BPs also showed antitumor properties in solid malignancies by inhibiting cancer cell proliferation, inducing apoptosis and affecting bone microenvironment, increasing progression free survival (PFS) and overall survival (OS). In head and neck squamous cell cancer, RANKL expression has been observed and correlated with tumour differentiation and progression. RANKL expression is also found in tumour-infiltrating Tregs. Once expressed, RANKL regulates epidermal dendritic cells and increases the number of Tregs, thereby suppressing excessive response to environmental stimuli. In NPC, the role of Tregs has been described and implicated in EBV-associated carcinogenesis. Although no direct evidence of denosumab activity in NPC cells are available, its target's effect on Tregs is at the base of an indirect effect to tackle cancer immune evasion. In this scenario, treatment with RANK and RANKL inhibitors will supposedly act as positive immunoregulator reducing bone events but also improving treatment effects. RANK expression was confirmed on 17 metastatic relapses of NPC treated at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. The recent introduction of denosumab, a new drug active on bone metastases, with a different mechanism of action compared to BPs, changed the scenario. Denosumab is a fully human monoclonal antibody preventing the binding of RANKL to its receptor on osteoclasts' membrane. Denosumab is formulated for SC injection and for oncology indications is administered at a dose of 120 mg Q4W. Denosumab (120 mg SC) is approved worldwide for the prevention of SREs in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with GCTB. The above premises warrant the investigation of the activity of denosumab - an antibody competing with RANK, enhancing increasing tumour-specific immunity through the blockade of RANKL-regulated Tregs.

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