Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer

SIMPLE SUMMARY: Immunotherapy offers new hope for patients with recurrent or metastatic head and neck cancer. However, only 20% of patients respond to this treatment. Combining radiotherapy in novel ways with immunotherapy can lead to synergistic effect by enabling cancer recognition by immune system and rendering tumor microenvironment less immunosuppressive. Based on a literature review, the main factors that need to be considered in future trials of immunoradiotherapy in head and neck cancer are discussed. The significance of proper timing of the treatment, the radiotherapy fractionation, patient selection, the number and the site of irradiated lesions, and the irradiated volume have been established in preclinical and clinical trials across different solid tumors. However, the trials using immunoradiotherapy in patients with recurrent or metastatic head and neck cancer have shown poor results so far and the reasons for this are elaborated on. ABSTRACT: Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.