Advances in Research on HPV-Related Oropharyngeal Cancer and Immunotherapy
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Advances in Research on HPV-Related Oropharyngeal Cancer and Immunotherapy
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Advances in Research on HPV-Related Oropharyngeal Cancer and Immunotherapy
Oropharyngeal squamous cell carcinoma (OPSCC), which includes cancers of the tonsils, base of the tongue, soft palate, and uvula, has historically been linked to alcohol consumption and smoking, much like other head and neck squamous cell carcinomas (HNSCC).
Over the past 20 years, smoking rates have declined in most developed countries, leading to a decrease in HNSCC incidence.
However, infection with carcinogenic human papillomavirus (HPV) has emerged as a significant risk factor, contributing to the rising incidence of OPSCC.
In fact, HPV-positive OPSCC has become one of the fastest-growing cancer types in developed nations.
The most recent edition of the American Joint Committee on Cancer (AJCC) staging system now categorizes HPV-positive and HPV-negative OPSCC as distinct entities, each with different molecular characteristics, tumor features, and clinical outcomes.
Due to the unique biology of HPV-positive OPSCC, immunotherapy has garnered considerable attention in recent years.
Below is a review of key advancements in the epidemiology, molecular mechanisms, clinical management, and especially the immunotherapy of HPV-positive OPSCC.
Epidemiology of HPV-Positive OPSCC
Among all cancers, OPSCC is one of the fastest-growing in incidence in developed countries. Its prevalence is rising in regions such as the United Kingdom, the United States, parts of Europe, New Zealand, and some areas of Asia. Notably, the incidence of oropharyngeal cancer in men in the U.S. and U.K. now surpasses that of cervical cancer in women.
In the past two decades, both HPV-positive and HPV-negative OPSCC incidences have risen, with the former increasing at a faster rate. For example, in Denmark, HPV-positive OPSCC incidence tripled between 2000 and 2017, compared to a two-fold increase in HPV-negative cases. Similarly, in Taiwan, there has been a more rapid increase in HPV-positive HNSCC, particularly tonsillar squamous cell carcinoma (SCC). In Italy, the incidence of HPV-positive OPSCC rose from 16.7% between 2000-2006 to 46.1% between 2013-2018.
Additionally, the prevalence of HPV-positive OPSCC is shifting towards older men. In one study, the median age at diagnosis increased from 53 years in 1998 to 58 years in 2013. Despite this shift, most cases still occur in individuals under 65.
Molecular Mechanisms of HPV-Positive OPSCC
HPV is a non-enveloped virus with a circular double-stranded DNA genome of about 8 kbp. Over 200 types of HPV have been identified, and all of them infect and replicate in skin or mucosal epithelium. The World Health Organization (WHO) classifies 14 mucosal HPV types, including HPV-16, 18, 31, 33, and others, as “high-risk” (hrHPV) due to their clear association with cancer. HPV-16 is responsible for at least 85% of all HPV-positive OPSCC cases.
HPV-driven carcinogenesis is primarily mediated by two viral early genes, E6 and E7, which act as oncogenes. Their main function is to trigger the epithelial basal cell cycle, allowing the virus to replicate its genome. The increased expression of E6 and E7 is often linked to the integration of hrHPV DNA into the host genome.
Clinical Management of HPV-Positive OPSCC
OPSCC typically presents with a neck mass or sore throat but may also manifest as difficulty swallowing, a visible mass, or referred ear pain. Most patients present with small primary tumors (T1 or T2) and lymph node metastasis. Clinical presentation can resemble other benign conditions, such as laryngopharyngeal reflux or globus sensation, which complicates diagnosis. Asymptomatic neck masses should ideally be evaluated using confirmatory ultrasound and fine-needle biopsy.
Distinguishing HPV-positive from HPV-negative OPSCC requires robust HPV testing. Immunohistochemical (IHC) staining for p16 and in situ hybridization (ISH) for high-risk HPV have shown high sensitivity (97%) and specificity (94%), allowing for effective diagnosis using formalin-fixed paraffin-embedded tissue samples.
Treatment options for OPSCC typically include surgical resection, primary radiation, or chemoradiotherapy. Historically, surgery involved open resection, but concerns over cosmetic and functional outcomes have led to the adoption of minimally invasive techniques for early-stage disease. When surgery is not feasible due to tumor size or other factors, primary radiation with concurrent chemotherapy, typically platinum-based such as cisplatin, is the standard of care.
Immunotherapy for HPV-Positive OPSCC
In HPV-positive malignancies, boosting the immune response against viral antigens (particularly those derived from E6 and E7) has been a long-sought goal in immunotherapy. Various immunotherapeutic approaches have been developed over the past 20 years for HPV-positive cancers. To date, however, only PD-1/PD-L1 antibodies have been approved for clinical use.
In 2016, based on results from phase III clinical trials CheckMate-141 and KEYNOTE-040, the FDA approved the PD-1 inhibitors nivolumab and pembrolizumab for use in patients with metastatic platinum-refractory HNSCC, regardless of HPV status. In 2019, pembrolizumab was also approved as a first-line therapy for PD-L1-positive metastatic or unresectable HNSCC based on results from the KEYNOTE-048 trial. These studies demonstrated improved objective response rates (ORR) and overall survival (OS) in HPV-positive patients. However, the precise relationship between HPV status and prognosis in the context of PD-L1 blockade remains unclear, highlighting the need for further research.
Several ongoing clinical trials are exploring novel combinations of immunotherapy and vaccines targeting E6/E7 in HPV-positive OPSCC. For instance, a phase II trial combining nivolumab with an HPV-16 E6/E7 peptide vaccine reported a 36% ORR and a median OS of 17.5 months. Additionally, DNA vaccines like MEDI0457 have shown promising results in inducing HPV-specific immune responses, which may lead to more durable responses in future clinical applications.
Conclusion
In the past two decades, the incidence of various head and neck cancers, such as oral and laryngeal cancers, has stabilized or slightly declined. However, the incidence of oropharyngeal cancer, particularly HPV-positive OPSCC, has risen significantly, especially among younger men.
Immunotherapy offers a promising approach to improving the survival rates of HPV-positive OPSCC patients. Further understanding of the molecular mechanisms and clinical progression of this disease will help identify biomarkers for diagnosis, prognosis, and treatment, paving the way for more effective immunotherapeutic strategies.
Advances in Research on HPV-Related Oropharyngeal Cancer and Immunotherapy
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