The clinical landscape of HPV vaccination in preventing and treating cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (cSCC) is a malignancy with rising global incidence and burden especially amongst the immunosuppressed. The human papillomavirus (HPV) has been strongly implicated as a risk factor for cSCC.¹ Hence, HPV vaccination may be a viable adjuvant to established practices in preventing and treating cSCC and its precancerous lesions (actinic keratosis [AK], Bowen's disease).² The study aimed to review clinical studies that investigated HPV vaccination in the prevention or treatment of cSCC and its precancerous entities. We conducted a systematic search of literature databases (PubMed, Embase, Scopus, Cochrane Library) on 16 May 2024 in accordance to PRISMA guidelines (Figure 1; PROSPERO registry number CRD42024550413). Article screening and data extraction were performed in duplicate. Full-text clinical studies published in English that investigated HPV vaccination in the prevention or treatment of cSCC and its precancerous entities in ≥1 patient were included. We identified four full-text clinical studies (Table 1). Firstly, systemic α-HPV vaccination (Gardasil-9®) demonstrated benefits in the secondary prevention of AK and cSCC amongst immunosuppressed adults with recurrent keratotic skin lesions. Nichols et al. reported substantial reduction (63%–88%) in post-vaccine keratinocyte carcinoma incidence in two patients.³ Bossart et al. noted fewer visits (0.7/year to 0.2/year, p < 0.05) with major dermatological interventions after vaccination in a larger cohort of 38 immunosuppressed adult patients with keratinotic skin lesions (warts, AK, Bowen's disease, cSCC), of which 21/38 have previous cSCC and/or AK.⁴ Secondly, systemic α-HPV vaccination (Gardasil-9®) displayed merit in the primary treatment of AK and cSCC in immunocompetent adults. Wenande et al. reported an 85% reduction in AK lesions after vaccination in 12 immunocompetent adult patients with high AK burden.⁵ Nichols et al. described a case of cSCC regression following combinatorial systemic and intratumoral α-HPV vaccination (Gardasil-9®) in an elderly immunocompetent patient.⁶ No local or systemic side effects were reported in all studies. Although promising, the studies were limited by small sample sizes, their observational nature, the lack of unvaccinated controls, and opacity regarding the patients’ HPV status. This hampers our understanding of vaccine response, especially since¹ better responders might have had mixed α- and β-HPV infections, and² better responders might have been colonized by β-HPV subtypes that are phylogenetically closer to α-HPV. Bossart et al. had also indirectly measured vaccination response through the number of dermatological interventions required in the postvaccination period. There is an ongoing Phase II trial on systemic α-HPV vaccination (Gardasil-9®) in the primary treatment of 70 immunocompetent adult patients with pre-vaccine high AK burden.⁷ However, the β-HPV-based vaccine landscape remains nascent with limited clinical data. There is an unmet need for β-HPV-based vaccines since β-HPVs are intimately associated with cSCC carcinogenesis and cross-protection conferred by commercially available α-HPV vaccines is largely against genetically-related types of α-HPVs and is often restricted against β-HPVs. The challenge with developing the first-generation β-HPV vaccine lies with our imperfect grasp of the human skin virome—we do not know the full extent of β-HPV subtype prevalence across individuals nor the subtypes that are associated with the highest oncogenic risk. Notwithstanding, there are active preclinical studies exploring β-HPV L1/L2-based and DNA vaccines.^8-10 In summary, α-HPV vaccination may be beneficial in the secondary prevention and primary treatment of cSCC and AK. More trials are warranted to prove the clinical utility of HPV vaccination in managing these diseases. In addition to clinical studies of experimental β-HPV-based vaccines, future work can further characterize the skin virome and virus-specific immune responses to optimize vaccine design.

Conceptualization: SHT, CCO; Data Curation: SHT, CCO; Formal Analysis: SHT, CCO; Methodology: SHT, CCO; Investigation: SHT, CCO; Writing - Original Draft Preparation: SHT; Writing - Reviewing and Editing: CCO.

The authors declare no conflict of interest.

Not applicable.