Research progress of HPV-related oropharyngeal carcinoma and immunotherapy

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Research progress of HPV-related oropharyngeal carcinoma and immunotherapy

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Research progress of HPV-related oropharyngeal carcinoma and immunotherapy. 

Oropharyngeal squamous cell carcinoma ( OPSCC ) includes carcinomas of the tonsils, base of the tongue, soft palate and uvula. Like other head and neck squamous cell carcinomas ( HNSCC ), OPSCC has historically been associated with alcohol consumption and smoking.

Reduced smoking rates in most developed countries have contributed to a decline in the incidence of HNSCC over the past 20 years; however, oncogenic human papillomavirus (HPV) infection has emerged as another important risk factor that contributes to the increase in the incidence of OPSCC Increase.

At present, human papillomavirus ( HPV )-positive OPSCC has become one of the fastest-growing cancer types in developed countries.

The latest version of the American Joint Committee on Cancer ( AJCC ) staging system defines HPV-positive and HPV-negative OPSCs as separate entities with distinct molecular features, tumor characteristics and clinical outcomes.

Due to the unique biological properties of HPV+OPSCs, immunotherapy has become a field of particular interest.

This article reviews the epidemiology, molecular mechanism, clinical management and important progress of HPV+OPSCC especially in the field of immunotherapy.

Epidemiology of HPV+OPSCC

Among all cancers, OPSCC is one of the fastest-rising cancers in the developed world. Incidence of the disease is rising in the UK, US, throughout Europe, New Zealand and parts of Asia. In both the UK and the US, the incidence of oropharyngeal cancer in men exceeds the incidence of cervical cancer in women.

The incidence of both HPV+ and HPV–OPSCC has increased over the past 20 years, with evidence that the former is increasing more rapidly. In Denmark, the incidence of HPV+OPSCC tripled from 2000 to 2017, while the incidence of HPV- tripled.

In contrast, faster growth of HPV+HNSCC, especially tonsillar squamous cell carcinoma ( SCC ), was observed in Taiwan. In Italy, the incidence of HPV+OPSCC increased from 16.7% in 2000-2006 to 46.1% in 2013-2018.

In addition, the prevalence of HPV+OPSCC has begun to shift to older men.

In one study, the median age at diagnosis increased from 53 to 58 between 1998 and 2013, while another study reported a similar increase, from 52 to 59 between 2002 and 2017. age.

Although the burden is shifting to the elderly, most cases still occur in people under the age of 65.

Molecular mechanism of HPV+OPSCC

HPV is a non-enveloped virus with a circular double-stranded DNA genome of about 8 kbp. More than 200 HPV types have been identified, all of which infect the skin or mucosal epithelium and complete their productive life cycle.

Of these, WHO currently classifies 14 mucosal HPV types ( HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 ) as “high-risk types” ( hrHPV ), since there is clear experimental and epidemiological evidence that they are associated with cancer etiology, HPV-16 accounts for at least 85% of all HPV+OPSCCs.

HPV+ carcinogenesis is primarily driven by two viral early genes ( E6 and E7, considered HPV oncogenes ) whose physiological function is to trigger cell cycle entry in the basal epithelium, thereby allowing viral genome replication. Increased expression of E6 and E7 is often associated with integration of hrHPV DNA into the host genome.

Many studies have provided insight into the molecular mechanisms by which E6 and E7 induce host cell entry into the cell cycle and DNA replication.

These effects, combined with alterations in the host genome, can lead to malignant transformation of host cells.

The two most characteristic oncogenic activities of E6 and E7 involve increased degradation of p53 and Rb, respectively.

Removal of these key tumor suppressor proteins results in loss of cell cycle checkpoint activation in response to DNA damage and uncontrolled DNA replication, both of which together lead to genomic instability and resistance to apoptosis.

Clinical management of HPV+OPSCC

OPSCC most commonly presents as a neck mass or sore throat, but may also present with dysphagia, visible mass, globus, dysphagia, or ear pain.

Most patients present with primary small tumors ( T1 or T2 ) and lymph node metastases.

In addition, the clinical presentation of OPSCC can easily be confused with other common benign conditions, such as laryngopharyngeal reflux or pharyngeal bulb; therefore, ideally, asymptomatic neck masses should be evaluated using confirmatory ultrasonography and fine-needle biopsy samples.

In order to accurately distinguish HPV positive from negative, robust HPV testing is required.

The combination of immunohistochemical ( IHC ) staining for p16 and in situ hybridization ( ISH ) for high-risk HPV has demonstrated acceptable levels of sensitivity ( 97% ) and specificity ( 94% ), and the use of formalin Lin-fixed paraffin-embedded tissue was assayed.

Treatment of patients with OPSCC usually includes surgical resection, primary radiation therapy, or chemoradiotherapy.

Historically, surgical resection has involved open surgery, however, this has been largely replaced by minimally invasive techniques for patients with early stage disease due to concerns about cosmetic and/or functional disease.

Primary radiotherapy and chemotherapy are also widely used if surgery is not technically feasible, such as due to large primary tumor diameter ( T3 or greater ), poor oral route, or advanced bilateral nodal disease. The current standard of care is 66-70 Gy radiotherapy with concurrent platinum-based chemotherapy, usually cisplatin-based.

Immunotherapy of HPV+OPSCC

In patients with HPV+ malignancies, promoting responses to viral antigens ( especially those derived from E6 and E7 ) or enhancing pre-existing antitumor immune responses is an attractive and long-sought immunotherapy prospect.

A variety of HPV+ cancer immunotherapy approaches have been developed over the past 20 years. However, to date, only anti-PD-1/PD-L1 antibodies have been approved for clinical use.

In 2016, the FDA first approved the anti-PD-1 antibodies nivolumab and pembrolizumab for patients with metastatic platinum-refractory HNSCC ( regardless of HPV status ) based on data from Phase III clinical trials CheckMate-141 and KEYNOTE-040.

In 2019, pembrolizumab was also approved as a first-line monotherapy for patients with PD-L1+ metastatic or unresectable HNSCC, based on data from the Phase III KEYNOTE-048 trial.

These trials all included patients with both HPV+ and HPV-, with three studies showing increased objective response rate ( ORR ) and improved OS in patients with HPV+ disease, including one showing that in the presence of PD-L1 blockade , the relationship between HPV status and prognosis was stronger, while another found no association between HPV status and prognosis.

Therefore, this underlines the need for further research on this important issue.

In the neoadjuvant setting, a phase Ib trial ( NCT03247712 ) of nivolumab in combination with stereotactic body radiotherapy ( SBRT ) produced a high pathological complete response ( pCR ) rate ( 67% ) in a cohort of 21 patients with locally advanced HNSCC , Of these, 16 had HPV+. The anti-PD-L1 antibody durvalumab in combination with SBRT is currently being tested in NCT03618134, a Phase Ib/II trial specifically targeting HPV+OPSCC patients.

In the neoadjuvant setting of CheckMate-358, where the effect of nivolumab monotherapy was also investigated, low radioresponse rates were observed in HPV-positive ( 12% ) and HPV– ( 8.3% ) patients. No pCR was found in this study, and among patients with HPV+ disease, only one of the 17 evaluated patients had a major pathological response (MPR), and three others had a partial pathological response.

In the phase Ib CIAO trial involving 28 patients with OPSCC , 24 of whom had p16+ tumors , 29% had MPR, and no increased benefit was observed with the addition of the anti-CTLA-4 antibody tremelimumab.

However, differences in the criteria used to assess pathological response make it difficult to compare data from these different neoadjuvant trials, and the rate of pathological response appears to be low in HNSCC patients treated with neoadjuvant anti-PD-1/PD-L1 antibody as monotherapy Pathological response rates in patients with several other cancers.

Therapeutic vaccines based on E6 and/or E7 have long been investigated for the treatment of cervical cancer, however, unfortunately, without any significant clinical success so far.

Several therapeutic vaccines targeting E6 and/or E7 have entered trials in HPV+OPSCC patients, and many studies are currently testing combinations with ICIs or other immunomodulators.

In a phase II trial of nivolumab in combination with the HPV-16E6/E7 peptide vaccine ( ISA 101 ), ORR was 36% in 22 HPV+OPSCC patients, with a mean OS duration of 17.5 months, compared with data from the nivolumab monotherapy trial has an advantage in comparison.

In a phase I/IIa trial of MEDI0457, a DNA vaccine encoding the E6 and E7 antigens of HPV-16 and HPV-18, in combination with nivolumab, 18 of 21 patients with locally advanced p16+ HNSCC induced durable HPV-specific Sexual immune response, including a complete rapid and durable response in one metastatic patient.

Other ongoing trials include HARE-40, a Phase I/II dose-escalation trial ( NCT03418480 ) designed to determine the safety of an E7-targeted mRNA vaccine in combination with an agonistic anti-CD40 antibody; and the first study of the novel E6/ Human Phase I/II trial of E7-targeted vaccine HB-201, with and without combined immune checkpoint inhibition (NCT0418015 and NCT03669718).

The results of these and other trials will be critical to advancing the continued progress of immunotherapy in patients with HPV+OPSCs.

Summary of “Research progress of HPV-related oropharyngeal carcinoma and immunotherapy”

In the past 20 years, the incidence of various head and neck tumors, including oral cancer and laryngeal cancer, has been stable or slightly decreasing, but the incidence of oropharyngeal cancer has been increasing, and the proportion of HPV+OPSCC is particularly obvious. male.

Due to the sensitivity of these tumors to antitumor immunity, immunotherapy is a very promising direction for improving morbidity and mortality.

Therefore, this requires a better understanding of the molecular basis and clinical course of this disease to identify and validate diagnostic, prognostic and predictive biomarkers to improve early detection rates and stratify patients to strengthen underlying immune treatment and ultimately improve patient outcomes.

References :

1. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol. 2022Feb 1: 1–22.

Research progress of HPV-related oropharyngeal carcinoma and immunotherapy. 

(source:internet, reference only)

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