Anti-Tumour TreatmentImmuno-oncology in head and neck squamous cell cancers: News from clinical trials, emerging predictive factors and unmet needs
Section snippets
Rationale for exploring immunotherapy in HN cancer
Head and neck cancers consist in a heterogeneous group of tumors with different natural history, that strictly depends on histology, anatomical site of origin and tumor biology. Well-known risk factors are alcohol abuse, tobacco smoking [1], and human papillomavirus (HPV) infection [2].
Head and neck squamous cell carcinoma (HNSCC), as many other cancers, develops in the context of immune suppression [3]. Indeed, a deregulated immune system in terms of cancer immunosurveillance is a key point in
What we learned from clinical trials till now
All the preclinical observations about the immunogenicity of HNSCC represent a strong rational to the use of immunomodulating strategies for overcoming immune deregulation in these patients. Involved inblocking the activity of chronically stimulated T cells and causing their functional exhaustion., immune checkpoint such as CTLA4 and PD-1 are over-expressed in HNSCC microenvironment [22]. Antibodies directed against PD-1/PD-L1 and CTLA4have been assessed also in the treatment of metastatic
Combination therapeutic strategies
Anti-tumor activity of immune checkpoint inhibitors used as monotherapy, in terms of both survival and response rate, is promising, but we are still far from achieving a satisfactory goal in managing platinum resistant HNSCC patients, whose prognosis remain dismal in the great majority of cases. The use of multiple immunotherapeutic agents, aimed at promoting more efficient immune responses and possibly overcoming additional escape mechanism, are being developed in RM setting.
Immunotherapy and radiotherapy
In locally advanced setting multiple therapeutic combinations of immunotherapy are also under investigation. Specifically, radiation therapy may increase the capability of the immune system to exert its function through an increase in tumor neoantigens, due to the mutagenic activity of radiation [53], boost in antigen presentation [54], enhanced killing by CD8+ T-cells [55] and improved cytokines production triggering a acute pro-inflammatory cascade [56]. DNA damage itself is a potent
Predictive factors of response
To date, no definite predictive factors of response have been identified for immunotherapy in HNSCC. Tumor tissue PD-L1 expression is associated with an immune-active microenvironment, thus theoretically it could be the strongest predictive factor of response to PD-1/PD-L1 inhibitors [68]. In line with the strong immunogenicity of this cancer, tumor tissue PD-L1 expression was observed in 45–80% of HNSCC [69].
Additional druggable pathways of tumor immune escape
As already mentioned, many are the mechanisms described to impair immune recognition in HNSCC [16]. In addition, a sort of specific phenotype that characterized HNSCC and possibly create a particularly immune suppressive microenvironment is related to the enrichment in cancer stem-like cells [84] which have been shown, together with signatures associated to epithelial to mesenchymal transition and hypoxia, to identify tumors resistant to immune checkpoint inhibitors. [85] The recruitment at
The unmet needs
In head and neck immuno-oncology, many are the unmet clinical needs. Among them is the identification of robust predictive factors to better select patients potentially benefitting from immune checkpoint inhibitors, so avoiding toxicities and applying alternative strategies to non-responding subjects.
In this regard, the choice should fall not only on molecular or circulating biomarkers, but also on clinical characteristics able to discover the responding patients.
The identification of a
Conclusions
The first encouraging results with checkpoint inhibitors involved recurrent or metastatic platinum-resistant disease.
The actual mainstays of the management of head and neck cancer in the curative setting are surgery and/or radiotherapy with or without chemotherapy. To date, no definitive data about the role of immune checkpoint blockade in HNSCC locally advanced disease are available. However, the promising data in adjuvant setting achieved in melanoma and the promising results in stage III
Conflicts of interest
Lisa Licitra reports grants and personal fees from Eisai, MSD, Boehringer Ingelheim, Novartis, Astrazeneca, Roche; personal fees from BMS; grants, personal fees and other (travel expenses) from Merck-Serono, Bayer, Debiopharm, Sobi.
Laura Locati reports honoraria from Eisai.
Paolo Bossi reports honoraria or consultation fees from Roche, Merck Serono, Mundipharma, Kyowa Kyrin, Astra Zeneca.
All remaining authors have declared no conflicts of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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