Human papillomavirus (HPV) vaccination has already transformed the clinical outlook for young women, with several EU countries now reporting sharp declines in cervical cancer incidence and mortality (article 1, 2, 3). As discussed in our previous article, some vaccinated birth cohorts are on track to see cervical cancer become a genuinely rare disease, raising an important question: could widespread HPV vaccination, including men, achieve similar success for other HPV‑driven cancers?
One such cancer is HPV‑positive oropharyngeal cancer (OPC), a subtype of head and neck cancer (HNC). HPV now behaves as an active cancer epidemic, particularly in Scandinavia, where the incidence of HPV-positive OPC among middle‑aged men has roughly tripled over the last three decades (article). Denmark now has one of the highest OPC incidence rates in the EU (article), and together with Sweden has among the highest proportions of HPV-positive OPC (article), underscoring how central HPV has become to the regional cancer burden.
Because both oral high-risk HPV infection and OPC are more common in men than in women (article), it is reasonable to ask: if gender-neutral HPV vaccination were widely introduced, would HPV-positive OPC incidence fall in future decades?
Some countries have taken the lead to answer this question, with UK, SE and DK introducing public vaccination programs in 2019/2020. However, because the vaccine is given at 11–12 years of age and HPV-positive OPC typically arises decades later at 60–65 years (article), measurable reductions in cancer incidence are unlikely to become apparent for many years (article).
This prolonged transition creates a substantial opportunity for treatment strategies tailored to HPV-positive disease, including systemic therapies, immunotherapy combinations and de-escalation approaches that may support distinct patent positions around patient selection, dosing and treatment sequencing.
Immunotherapy and biomarkers in HPV-positive head and neck cancer
HPV-positive OPC is biologically distinct from tobacco and alcohol-induced OPC and is generally associated with a better prognosis (article). In part, this is stems from the fact that HPV viral antigens can serve as targets for the immune system (article 1, 2), making precise modulation of antitumour immunity a particularly attractive therapeutic strategy.
2017 marked a major shift in HNC treatment with the EMA approval of the first anti-PD1 immune checkpoint inhibitors for recurrent or metastatic (r/m) disease (article). By blocking the PD1 immune checkpoint, these antibodies release inhibitory signals on T cells and enhance antitumour immunity.
Because HPV-positive OPC expresses viral antigens, many expected these agents to deliver greater benefit in HPV-positive than HPV-negative disease. However, CheckMate 141 demonstrated broadly similar survival outcomes across HPV subgroups. Even so, anti-PD1 therapy has improved outcomes in selected r/m HNC populations (PD-L1+ patients) and now acts as the preferred clinical platform for newer therapeutic strategies in HNC, and therefore in HPV-positive OPC.
Nivolumab and pembrolizumab’s IP lifecycle management synergizes with their clinical success to ensure a strong market position for PD1 inhibitors. In practice, this rests first on the core compound patents for pembrolizumab and nivolumab which are expected to expire in 2028 in EU. SPCs and related paediatric extensions may extend effective exclusivity into the early 2030s. On top of this, patents covering subcutaneous formulations of their PD1 inhibitors may further extend their protection into the late 2030s-2040. These overlapping layers of protection form a classic patent thicket: a dense web of rights that delays biosimilar market-entry and reinforces pembrolizumab and nivolumab’s role as the preferred clinical platform in this indication. For companies developing new compounds, early assessment of SPC eligibility and routes of incremental innovation are key in shaping both exclusivity strategy and commercial value.
As a result, current development is focused on building upon anti-PD1 success rather than replacing it. In HPV-positive OPC, the next phase of clinical development is pursuing two complementary strategies:
- enhancing the efficacy of PD1 blockade through rational combinations that stimulate complementary immune mechanisms, and
- moving immunotherapy into earlier disease stages where it may enable treatment de-intensification.
Key approaches include therapeutic cancer vaccines, immune modulators, and combinations with de-intensified chemoradiation.
Combination strategies in recurrent/metastatic disease
Several programs are competing to become the preferred add-on to pembrolizumab in the first-line setting, most notably PDS Biotech’s PDS0101 (NCT06790966), BioNTech’s BNT113 (NCT04534205), Immutep’s Efti (NCT04811027), Merus’s Petosemtamab (NCT06525220), and Bicara’s Ficerafusp alfa (NCT06788990).
Among HPV-specific therapeutic vaccines in r/m HNC, PDS0101 and BNT113 are currently among the most advanced. The two platforms differ in both antigen delivery and antigen format:
- PDS0101 is a cationic liposomal nanoparticle vaccine that directly delivers selected HPV16 E6/E7 peptides with an immunostimulatory lipid, providing a fixed set of defined epitopes.
- BNT113 is an RNA-lipoplex vaccine that delivers mRNA encoding HPV16 E6/E7, enabling host cells to transiently synthesize and process the antigens.
Preliminary phase II data suggest that both approaches increase the overall response rate, broadening the patient population addressable by pembrolizumab in HPV16+ r/m HNSCC. Phase III readouts are expected to clarify their clinical potential. Conceptually, PDS0101 might show more local reactogenicity and cytokine‑type symptoms due to its lipid component but could induce strong responses to carefully selected epitopes. By contrast, BNT113’s RNA platform could generate a broader epitope repertoire which may enhance depth and breadth of T‑cell responses. However, differentiation may depend not only on clinical efficacy but also on how specifically the platform, antigen design, immune-stimulatory components and combination regimen are protected.
Biomarker guided de-escalation in locally advanced HPV-positive OPC
Immune checkpoint inhibitors are moving beyond the metastatic setting into curative-intent treatment, where their integration with standard of care is still being defined. KEYNOTE-689 marks an inflection point, leading in 2025 to the first approval for resectable locally advanced HNC in two decades.
The next challenge is to determine how immunotherapy can improve outcomes while personalising treatment intensity. This is particularly important because current standard-of-care regimens can cause lasting impairments in speech, swallowing and quality of life.
In HPV-positive OPC, response-adapted strategies are emerging as a potential solution, using early indicators of tumour response to guide treatment de-escalation. The OPTIMA II and TARGET-HPV studies are evaluating whether biomarkers such as circulating tumour HPV DNA (ctHPV) can identify patients who may safely undergo de-intensification.
OPTIMA II illustrates this approach, sequentially combining neoadjuvant PD1 blockade plus chemotherapy, ctHPV assessment and response-adapted local radiotherapy. The data suggest that ctHPV clearance identifies patients suitable for reduced treatment intensity and, that the combination and dosing regimen improve tolerability and quality of life outcomes while maintaining efficacy.
Together, these trials illustrate a broader shift in oncology: biomarkers are moving from prognostic tools toward active treatment selection platforms, enabling adaptive dosing, individualised treatment intensity and potentially protectable clinical decision pathways based on ctHPV dynamics.
Looking ahead
As PD1 blockade becomes an established foundation for treatment, the next wave of value in HPV-positive OPC may come from technologies that determine which patients receive which treatment, when, and at what intensity. For innovators, this shifts the protection strategy beyond new therapeutic agents alone, bringing SPC eligibility, lifecycle management, combination regimens, biomarker-guided patient selection and ctHPV-based treatment algorithms into sharper focus.
About the author
David Gomez Jimenez is a patent consultant specialising in immunology, oncology and precision medicine. He advises clients on protecting life sciences innovations across therapeutic antibodies, patient stratification and data driven technologies.
If you are developing therapeutic, diagnostic or biomarker-led approaches in this space and would like to explore how intellectual property could support your innovation, please get in touch.
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