Abstract
Head and neck squamous cell carcinoma (HNSCC) represents a model of escape from anti-tumor immunity. The high frequency of p53 tumor suppressor loss in HNSCC leads to genomic instability and immune stimulation through the generation of neoantigens. However, the aggressive nature of HNSCC tumors and significant rates of resistance to conventional therapies highlights the ability of HNSCC to evade this immune response. Advances in understanding the role of co-stimulatory and immune checkpoint receptors in HNSCC-mediated immunosuppression lay the foundation for development of novel therapeutic approaches. This article provides an overview of these co-stimulatory and immune checkpoint pathways, as well as a review of preclinical and clinical evidence supporting the modulation of these pathways in HNSCC. Finally, the synergistic potential of combining these approaches is discussed, along with an update of current clinical trials evaluating combinations of immune-based therapies in HNSCC patients.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, affecting over 500,000 people each year [1]
This poor prognosis despite advances in chemotherapy, radiation, and surgical protocols highlights the need for treatments with greater efficacy in the Human papillomavirus (HPV)- population, and improved toxicity profiles for HPV+ patients
In vitro studies of agonistic CD40 monoclonal antibody (mAb) induced Antigen-presenting cell (APC) activation and maturation, and recombinant CD40L increased the ability of APCs to cross-prime naïve T-cells to tumor antigens [26, 27]
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, affecting over 500,000 people each year [1]. In vitro studies of agonistic CD40 mAb induced APC activation and maturation, and recombinant CD40L increased the ability of APCs to cross-prime naïve T-cells to tumor antigens [26, 27] These data suggest a role for this approach in augmenting responses to tumor vaccines, which has been demonstrated in a murine solid tumor model [28]. A variety of CD40-targeting therapies have been developed, including agonistic mAbs and recombinant ligands This approach has not been studied in the HNSCC population, one HNSCC patient treated in a phase I trial of recombinant CD40-L experienced a durable and complete response [29]. Based on the promising preclinical data combining anti-OX40 treatment with surgery [36], a phase Ib trial of OX40 agonistic mAb MEDI6469 prior to definitive surgical resection is currently recruiting patients with locoregionally advanced HNSCC (NCT02274155). Extracellular binding of cetuximab to EGFR exposes the constant region (Fc) of cetuximab to binding by the
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