Abstract
Simple SummaryImmunotherapy 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.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.
Highlights
Head and neck cancers account for 3–5% of cancer cases with a 5-year overall survival rate of around 50–65% across all stages in the developed world [1,2,3,4,5]
In this review we present the biological rationale for combining anti-PD-1 with RT in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) and explore the details and formulate recommendations that need to be taken into consideration in design of future clinical trials
Trial the proportion of responding patients with was higher in the plus to immune checkpoint inhibitors (ICI), locally ablative RT added to ICI could lead to more pronounced synergistic effects by greater nivolumab arm compared to nivolumab only arm, suggesting that less inflamed tumors could reduction of disease burden in human papilloma virus (HPV)+ OP cancer patients [94,99]
Summary
Head and neck cancers account for 3–5% of cancer cases with a 5-year overall survival rate of around 50–65% across all stages in the developed world [1,2,3,4,5]. Even though HNSCC are among the most immune-infiltrated cancers still less than half of HNSCC are so called inflamed tumors, characterized by ample TILs, inflammatory response, cytolytic activity, and IFN signaling. This immune class of HNSCC can be further dissected into exhausted and active subtypes, with latter having significantly favorable prognosis and showing higher responses to anti-PD-1. These tumors are more likely to be normoxic and be of an inflamed/mesenchymal subtype of human papilloma virus (HPV) mediated tumors [28,29,30,31,32]. Inhibition of the PD-1/PD-L1 axis in HNSCC can lead to compensatory upregulation of alternative immune checkpoints, such as TIM-3, LAG-3, CTLA-4, TIGIT, GITR, and VISTA [48,49]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have