Cancer immunotherapy (CIT) is among the most important developments in cancer treatment over the last two decades. Despite the impressive successes in CIT, the response in patients is often limited and short lived. This is mainly due to multiple tumour-mediated immune escape mechanisms in addition to the short-lived anti-tumour effect due to the exhaustion and terminal differentiation of tumour-specific CD8 T cells.

The incidence of Head and Neck cancer varies between countries depending on risk factors. Overall, the incidence is on the rise which is attributed to changes in alcohol and tobacco consumption and human papilloma virus (HPV) infection. The latter is particularly important among younger patients affected by this disease. Tumours positive for HPV over-express the viral E6 and E7 antigens which can be recognized by the immune system and can therefore be used as targets for initiation of immune responses and effective immunotherapy. Recent studies suggest that the T cells responsible for tumor regression in HPV positive tumors do not recognize viral antigens but rather tumor neoantigens or germline antigens. Promising anti-tumour efficacy in murine HPV16 E7 antigen-expressing tumour model, using different formulations of E7 peptide vaccines has been reported. This therapeutic efficacy can be significantly enhanced when combined with different immune modulators such as small molecule inhibitors (e.g. PI3k-Akt pathway inhibitors), together with antibodies or molecules that target immune checkpoint inhibitors (such as PD-1, PDL-1 and CTLA-4) or agonize co-stimulatory molecules (such as OX40 and GITR). Alternatively a strategy of depleting suppressive myeloid cells produced improved T cell responses both in patients and animal models. These combination immune therapies might provide a promising treatment for HPV positive head and neck cancers as well as other HPV positive malignancies.

Despite the great excitement and important clinical benefit associated with agents that target the interaction of PD-1 and PD-L1 the majority of patients do not benefit from this therapy. Agonistic T cell antibodies directed at GITR and OX-40 have entered clinical trials and exciting results in preclinical animal models await clinical translation.
HPV antigens are just an example of a wide array of antigens aberrantly expressed in head and neck cancers. Therefore, cancer immune therapies, whether vaccine or cell therapy based provide a rich field of study and indeed great potential in providing curative personalized therapies for many patients suffering from these malignant diseases.

Several clinical trials that are testing the potential of cancer immunotherapy in head and neck cancers, and some of the FDA approved therapies for other malignancies are being adapted to these cancers. Additionally, multiple groups are studying the pre-clinical efficacy of new combinations while deciphering the exact mechanisms of action of various therapies.

There is great potential in combining different treatments including immunetherapeutics, cytotoxic chemotherapy and radiotherapy. It is therefore important to understand the interaction between different agents. Additionally, is important to assess the efficacy of different schedules when combining multiple immunotherapeutic agents (such as immune checkpoint inhibitors and cancer vaccines), in addition to traditional cytotoxic chemotherapy and radiotherapy.

The focus of this Research Topic is therefore the research being performed on head and neck cancers at the pre-clinical, translational and clinical levels. This can be in the form of original articles, systematic reviews, case reports and review articles.

The areas of interest include but are not limited to:

• Initial reports on clinical trials studying immune therapies in head and neck cancer patients (PD-1, PD-L1, and CTLA4 directed therapy; OX-40; GITR)
• Immune escape mechanisms in head and neck cancer
• HPV positive head and neck cancers as targets for immunotherapy
• Immune checkpoint inhibitors in head and neck cancer
• Biomarkers in head and neck cancer
• Different vaccine formulations in head and neck cancer
• Immune modulation in head and neck cancer
• Combination therapy using immune-radiotherapy
• The interaction between cancer immunotherapy and cytotoxic chemotherapy
• Sequencing treatment when combining different cancer therapeutics
• Identification of targets for immune therapy in head and neck cancer
• T cell directed therapy for HPV positive malignancies

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