Integrating Immunotherapy into Multimodal Treatment of Head and Neck Cancer

Abstract

Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis, with a significant risk of progression or death despite multimodal treatment with surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitors targeting the programmed death receptor-1 (PD1) have dramatically changed the treatment landscape for recurrent/metastatic disease, improving overall survival in both the first- and second-line palliative settings. This success has driven the investigation of treatment strategies incorporating immunotherapy earlier into the multimodal curative-intent or salvage treatment of both locally advanced and recurrent/metastatic HNSCC. This review encompassed the following three subjects, with a focus on recently reported and ongoing clinical trials: (1) the use of neoadjuvant immunotherapy prior to surgery for locally advanced HNSCC, (2) the use of immunochemoradiotherapy for locally advanced head and neck cancers, and (3) novel uses of immunotherapy in the salvage of recurrent/metastatic HNSCC via a combined modality, including reirradiation paradigms. The results of these studies are eagerly awaited to improve patient outcomes in this challenging disease.

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

“…The current findings demonstrate that MUC1 is upregulated in metastatic HNSCCs that are derived from barrier stratified squamous epithelial cells ( 8 ). Advanced HNSCCs invariably become refractory to multimodality treatment with chemotherapy, radiotherapy, and immunotherapy in association with development of DNA damage resistance and immune evasion ( 3, 63, 64 ). In regard to novelty, the current studies uncover involvement of MUC1-C in contributing to HNSCC cell intrinsic pathways of chronic inflammation.…”

“…These poor outcomes were substantially improved with development of (i) the immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab as single agents for the second-line treatment of platinum-refractory recurrent/metastatic disease and (ii) pembrolizumab alone or in combination with chemotherapy for first-line treatment ( 5–7 ). Those advances for treating HNSCC with immunotherapy fueled trials to evaluate immunochemoradiotherapy and other combined modalities ( 3 ). Nonetheless, intrinsic and acquired resistance has remained a challenge for HNSCC immunotherapy as patients invariably succumb to metastatic disease ( 3 ).…”

“…Those advances for treating HNSCC with immunotherapy fueled trials to evaluate immunochemoradiotherapy and other combined modalities ( 3 ). Nonetheless, intrinsic and acquired resistance has remained a challenge for HNSCC immunotherapy as patients invariably succumb to metastatic disease ( 3 ). The progression of HNSCC refractory to chemotherapy and ICIs has emphasized a need for the identification of druggable targets to circumvent DNA damage resistance and immune evasion.…”

A novel immune-related prognostic model with surgical status to predict tumor immune cell infiltration and drug sensitivity in head and neck squamous cell carcinoma

“…Males have substantially higher incidence and mortality rates than females [ 3 , 4 ]. Although multi-modal treatments such as surgery, chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICI) were used in patients with HNSCC, the overall survival (OS) remains disappointing, especially in those with locally-advanced lesions [ 5 ]. Hence, investigating the molecular mechanisms and potential biological markers associated with HNSCC tumorigenesis, disease progression, and treatment response remains challenging but presents opportunities for a better understanding of the disease [ 6 ].…”

“…However, surgery and radiochemotherapy could substantially disrupt tissues and vessels and change the TIC component in HNSCC, exacerbating preexisting immunosuppressive effects [ 5 , 7 ]. The OS prediction accuracy of previously published models was established based on immune-related signatures, and the usefulness of tumor stage and grade was limited in patients with HNSCC.…”