Enhancement of HPV therapeutic peptide-based vaccine ...

ABSTRACT

Human papillomavirus (HPV) has been linked to the development of various cancers, including head and neck, cervical, vaginal, penile, and anal cancers. The development of therapeutic vaccines against HPV-positive tumors is crucial for protecting individuals already infected with HPV, preventing tumor progression, and effectively treating the disease. The HPV therapeutic peptide-based vaccines demonstrate specificity and safety advantages by targeting specific epitopes while minimizing the risk of allergic or autoimmune reactions. However, HPV therapeutic peptide-based vaccines typically lack immunogenicity and frequently fail to induce effective immune responses. Therefore, there is a need for more effective approaches to improve the immunogenicity of HPV peptide-based vaccines. Here, we review relevant research and possible uses for increasing the immunogenicity and therapeutic efficacy of HPV peptide-based vaccines through combined therapy and improved delivery strategies. Additional research is necessary to validate the application of combination therapy and delivery strategy modifications as standard treatment approaches for HPV therapeutic peptide-based vaccines.

KEYWORDS: Human papillomavirus, peptide-based vaccines, combination therapy, tumor, immunogenicity

GRAPHICAL ABSTRACT

Introduction

Cervical cancer (CC) is a serious public health problem threatening women’s health. Human papillomavirus (HPV) infection is the most common cause of CC. HPV infection can improve patient outcomes through early diagnosis, prevention of infection, more effective treatment, and consideration of specific patient circumstances such as pregnancy status. This requires a comprehensive assessment of the patient’s health status, disease stage, and treatment options to develop the most appropriate treatment plan.1 Through screening and management of CC and the recommendation of prophylactic HPV vaccination, the incidence of CC caused by HPV has significantly decreased in recent years.2 Several studies have shown that the HPV vaccine not only prevents new infections, but also reduces the risk of reinfection or reactivation by inducing long-term immunity. This finding is particularly important for patients who have undergone hysterectomy, as they remain at risk for lower reproductive tract lesions.3 To prevent HPV infection, currently used preventive vaccines mainly induce the host to produce humoral immune responses, resulting in the generation of neutralizing antibodies, but cannot clear existing infections. However, HPV therapeutic vaccines induce the production of Th1-based cellular immune responses, clear existing infections and prevent the occurrence of precancerous lesions and cancer. Currently developed therapeutic vaccines transport E6 and E7 antigens to antigen-presenting cells (APCs) in different forms, which then trigger the activation of HPV antigen-specific CD8+ T cells and CD4+ helper T cells, respectively, stimulating the host specific anti-tumor immune response.4 Based on different antigen forms, HPV therapeutic vaccines can be divided into live vector vaccines (bacterial/viral vector vaccines), peptide or protein vaccines, nucleic acid vaccines (DNA/RNA vaccines), and cell vaccines.5

Therapeutic HPV vaccines have been the topic of two Phase III clinical trials. One such vaccine is the MVA E2 vaccine, a viral vector vaccine that utilizes the MPV E2 antigen to stimulate immune responses with cross-reactivity and to provide protection. The phase III clinical trial results indicated that of 1176 female and 180 male participants with HPV infection, cervical intraepithelial neoplasia was successfully eradicated in a significant proportion of female patients (89.3%). Moreover, approximately 81% of female patients effectively eliminated HPV from their bodies. Remarkably, all male patients achieved complete elimination of the lesions, while only a minimal number (five individuals) experienced recurrence within the five-year follow-up period.6 Another promising finding was observed in clinical trials investigating VGX-3100, an innovative therapeutic DNA vaccine designed to specifically target modified versions of the E6 and E7 viral proteins associated with HPV infection.7 The clinical trial Data from phase III clinical trials of these two therapeutic HPV vaccines provide hope for advancing therapeutic HPV vaccines. However, there are some limitations in the phase III clinical trials of both therapeutic HPV vaccines. The sample size of the VGX-3100 vaccine trial was insufficient, and the credibility of the test results for the MVA E2 vaccine trial was compromised owing to the absence of a control group.7

The development and deployment of HPV therapeutic vaccines are currently impeded by several pivotal challenges. Foremost among these are the difficulties in attaining effective expression and antigen presentation of HPV within appropriate cell types, the restricted serotype coverage of available vaccines, and the technical impediments associated with administering vaccines to mucosal surfaces such as the anogenital and upper respiratory-digestive tracts. Additionally, there is an urgent necessity to establish optimal vaccination regimens and integrate therapeutic vaccines with other treatment modalities to enhance their therapeutic benefits. Furthermore, there is a significant exigency to expand the evidence base for the efficacy of therapeutic vaccines in patients with advanced, recurrent, or intractable malignancies.7–9 To surmount these obstacles, future research endeavors should center on refining vaccine design to improve expression and antigen presentation within target cells, broaden the serotype coverage of therapeutic vaccines to address a more comprehensive range of HPV types, and develop innovative delivery mechanisms tailored for mucosal administration. It is also crucial to conduct rigorous clinical trials and leverage big data analytics to determine the most efficacious vaccination schedules and explore combination therapies. By targeting these areas of research, we can anticipate a gradual alleviation of these limitations, paving the way for a more extensive and impactful application of HPV therapeutic vaccines.

In HPV therapeutic vaccines, peptide-based vaccinations have attracted considerable attention as promising approaches for developing effective treatments, mainly because of their perceived safety, ease of production, and effectiveness. This review aimed to introduce how to enhance the efficacy of HPV peptide vaccines by combining them with other treatment methods or by improving delivery methods.

Survey methodology

To locate all publications published prior to June 2024 and ongoing clinical trials registered before June 2024, we performed searches in PubMed, Cochrane, Embase, and U.S. ClinicalTrials.gov. The search parameters included all terms associated with “HPV peptide vaccines,” “therapeutic HPV vaccines,” “HPV-associated precancerous lesions” and “HPV-related tumors.” We also cross-checked the references of the research included to ensure thorough coverage during our online investigation. The inclusion criteria consisted of: 1) being a clinical study; 2) involving patients with HPV-related cancers or HPV-associated precancerous lesions; 3) including at least one patient cohort receiving vaccinations based on HPV peptides; and 4) documenting at least one positive clinical result from combination therapy. Articles were excluded if: 1) there was no enhancement in the effectiveness of HPV peptide-based vaccines in any capacity; 2) they were released in a language other than English.

HPV peptide-based vaccines

Subunit vaccines are considered safer and less toxic because of their shorter half-lives in host organisms. It is a form of vaccine obtained by expressing the structural genes of microorganisms in vitro through recombinant DNA technology to produce peptides and proteins. HPV peptide-based vaccines are developed through in vitro synthesis of polypeptides, which involves the identification and characterization of the amino acid sequences of crucial antigenic epitopes on infectious pathogens. HPV peptide-based vaccines are convenient to prepare and easy to control.10 However, their effectiveness is limited by the need to match the corresponding human leukocyte antigen (HLA) type and major histocompatibility complex (MHC) limitations.11 These factors restrict the widespread implementation of mass vaccinations. Additionally, given their limited ability to trigger an immune response, they often need to be combined with adjuvants or fusion proteins to enhance their efficacy.

Currently, various HPV polypeptide vaccines have entered clinical trials, such as the HPV 16 E6 synthetic peptide (E61–45, E646–80, E681–115, and E6116–158) and the new adjuvant Candida albicans skin test antigen (Candin) polypeptide vaccine PepCan, which can promote T cell expansion and induce IL-12 secretion by Langerhans cells in phase I clinical trials.12 In a phase II study with a placebo control and double-blind design, a low-dose HPV16 synthetic long peptide vaccine (HPV16-SLP) was found to induce HPV16-specific T-cell responses and establish lasting immune memory in individuals with low-grade cervical lesions.13 Another study found that the HPV16-SLP vaccine is well-tolerated in individuals with advanced or recurring HPV16-induced gynecological cancer and induces broad IFN-γ-related T-cell responses.14 GL-0810 is an HPV-16 specific polypeptide vaccine prepared with a granulocyte-macrophage colony-stimulating factor and a montanide adjuvant for subcutaneous administration to treat recurrent/metastatic squamous cell carcinoma of the head and neck. The safety of GL-0810 was validated in a phase I study in which the dosage was gradually increased, and vaccinated patients showed T-cell and antibody responses.15 PDS0101 is a lipid-formulated therapeutic vaccine for HPV created using HPV-16 E6/E7 peptides. They included the immune-stimulating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides. A phase I study has demonstrated the in vivo induction of CD8+ T cells and their safety. Its therapeutic safety and tolerability are currently being evaluated in females with high-risk HPV infections and CIN 1 (NCT02065973, Phase I).16 Furthermore, the therapeutic vaccine DPX-E7 is currently being investigated in clinical trials for individuals with HPV-16 E7 and HLA-A *02 positive oropharyngeal, cervical, and anal cancers (NCT02865135, Phase Ib/II).17 Research on polypeptide vaccines has demonstrated their significant potential for clinical application.

Enhancing the therapeutic efficacy of HPV peptide-based vaccines

Enhancing the therapeutic efficacy of HPV peptide vaccines is a critical issue that requires immediate attention and rigorous investigation within academic and scientific communities. Enhancing the immunogenicity of HPV peptide vaccines can be achieved through strategies such as improving peptide size or conjugation properties, direct activation of APCs, or co-stimulation with adjuvants, and utilizing effective peptide delivery systems to promote endocytosis and phagocytosis. Additionally, introducing post-translational modifications in to HPV peptide-based vaccines further enhances their efficacy. All the strategies discussed in this article, which are anticipated to improve the efficacy of HPV peptide vaccines, can be found in Table 1.

Table 1.

Strategies for improving the efficacy of HPV therapeutic peptide-based vaccines.

Author	Year	Strategy	Outcome
Wu et al.	2010	PADRE peptide combined with poly(I:C) and peptide-based vaccines	Generate a strong antigen-specific CD8+T cell immune response and anti-tumor effect
Marij et al.	2016	Combination of CarboTaxol and HPV16-SLP vaccine	Stimulate a strong vaccine-induced T cell response and reset the abnormal myeloid cell composition induced by tumors to normal levels
Mariette et al.	2016	Imiquimod with ISA101 for combined therapy	The intensity of specific T cell immune response has increased
Zhao et al.	2017	Self-assembled nanoparticle delivery of peptide-based vaccines	Overcoming the low immunogenicity of peptide antigens, without causing adverse reactions
Xiang et al.	2018	Polystyrene nanoparticles (PSNPs) serve as a carrier for peptide-based vaccines.	Stimulate and enhance CD8+ T cell immune response
Erminia et al.	2018	Nivolumab combined with HPV16 peptide vaccine	Compared to the use of PD-1 inhibitors as monotherapy, there has been an improvement in overall response rates and median overall survival
Song et al.	2020	BHSSC extract and its active compound rutin are used as adjuvants for peptide-based vaccines	Enhance the anti-tumor activity in prevention, treatment, and recurrent HPV-related tumor models
Claire et al.	2020	PDS0101 vaccine in combination with bintrafusp alfa and NHS-IL12 for treatment	Induce tumor-associated T cell responses, enhance immune responses in the TME, and reduce immune suppression in the TME
Zahra et al.	2020	L1 protein-based HPV peptide vaccine	Induction of humoral and cell-mediated immunity
Tone et al.	2021	PCI vaccine combined with adjuvant poly-ICLC (Hiltonol)	Enhance cellular and humoral immune responses
Frank et al.	2022	TLR 2 ligand combined with HPV 16-SLP	Effectively inducing vaccine-specific T cell immunity
Chen et al.	2023	Delivery of peptide-based vaccines via bacterial outer membrane vesicles	Induce HPV tumor-specific CD4+ Th1 and CD8+ CTL responses, thereby effectively inhibiting the growth of HPV tumors

Improved delivery

Peptide-based subunit vaccines are generally successful in eliciting antibody responses but often fail to generate cellular immune responses, especially CD8+ T cell responses. One significant factor contributing to this may be the inadequate presentation of vaccine antigens introduced from outside MHC class I molecules on APCs. Photochemical internalization (PCI) is an innovative method for delivering drugs to the cytoplasm of cells in a minimally invasive manner. This technique facilitates the delivery of therapeutic molecules to target cells. PCI can be employed to augment the efficacy of current anticancer medications and new nanoparticle formulations to combat breast and pancreatic cancer cells.18 Preclinical experiments have indicated that utilizing the PCI technique with the photosensitizing agent TPCS2a can improve MHC class I antigen presentation, significantly enhancing CD8+ T cell responses to peptide antigens.19 In a phase I study without blinding, the combined administration of PCI peptide-based vaccination with adjuvant poly ICLC (Hiltonol) was demonstrated to be safe and capable of enhancing both humoral and cellular immune responses.20

Additionally, the development of peptide vaccines utilizing advanced nanoparticle delivery systems aims to ensure the proper processing of antigens into MHC class I-restricted epitopes to stimulate CD8+ T cell activations. Xiang et al. indicated that when HPV peptide vaccines are ineffective in generating the desired CD8+ T cell specificity with conventional adjuvants, nanoparticle-based methods such as polystyrene nanoparticles (PSNP) could provide an alternative vaccination method.21 Self-assembling nanostructured vaccines have been used to create HPV peptide vaccines. This delivery system, based on polymers, lipids, and peptides, can address the issue of low immunogenicity associated with peptide antigens while avoiding any negative reactions.22 Chen et al. pioneered a technique that integrates peptides and delivery systems by utilizing an innate bacterial secretion mechanism. They created an antigenic peptide within the bacteria cells through enzymatic processes, and subsequently discharged it into the extracellular environment using vesicles secreted by the bacteria, thereby accomplishing simultaneous peptide biosynthesis and transportation. This approach for delivering HPV peptide-based vaccines has been shown to induce HPV tumor-specific CD4+ Th1 and CD8+ cytotoxic T lymphocyte (CTL) responses in mice with tumors, effectively inhibiting the growth of HPV tumors.23 These innovations have advanced the HPV peptide-based vaccine biosynthesis field and expanded its potential applications.

Improved vaccine adjuvants

As a component of the strategy for developing vaccines, certain weakly immunogenic vaccines incorporate adjuvants to potentiate immune responses against antigens, thereby enhancing vaccine efficacy. Several studies have suggested that traditional Chinese medicine extracts can act as adjuvants to stimulate humoral and cellular immune responses in diverse vaccine approaches.24–27 Song et al. provided evidence that the extract of Hedyotis diffusa, along with its active compound rutin, can serve as adjuvants in HPV peptide vaccines to enhance immunogenicity. In vivo studies have demonstrated that Hedyotis diffusa can boost the responses of specific effector cells and memory T-cells. The concurrent use of HPV peptide vaccines and Hedyotis diffusa can improve anti-tumor effects in various models of preventive, therapeutic, and recurrent HPV-related tumors.28

In recent times, there has been an increasing use of Toll-like receptor (TLR) agonists as adjuvants. TLRs are a set of pattern recognition receptors (PRRs) that have the ability to activate the innate immune system by means of pathogen-associated molecular patterns (PAMPs), thereby enhancing antigen presentation by APCs.29,30 Given the natural role of TLR-4 in controlling various infectious diseases, a plethora of adjuvants targeting TLR-4 have been developed. Some of these adjuvants can be utilized for commercial vaccines against HPV and can augment vaccine responsiveness through optimal APC activation.31–33 Zahra et al. employed RS09 as an effective synthetic peptide agonist for TLR-4, which, through its interaction with TLR-4, promoted cellular and humoral immune responses, ultimately resulting in the design of a potent HPV peptide vaccine based on the L1 protein.34 Frank et al. conducted a phase I human trial to study a molecularly optimized TLR 2 ligand capable of covalently conjugating to tumor peptide antigens. When bound to HPV 16-SLP, this ligand can be safely utilized as an intradermal therapeutic peptide vaccine for HPV and trigger potent T- cell immunity directed specifically at HPV16.35 Wu et al. investigated the combination of an HPV-16 E7 peptide vaccine with a method involving the use of a pan-HLA-DR epitope (PADRE) peptide to augment CD4+ T helper cells, along with a strategy utilizing the TLR 3 ligand poly (I:C) to enhance dendritic cell activation. Their findings demonstrated that the co-administration of the PADRE peptide and poly (I:C) with the antigen peptide elicited robust targeted immune responses by CD8+ T cells and antitumor effects in mice that received the vaccine. These studies have important clinical implications for therapeutic peptide-based vaccination of HPV.36

Immune regulation

The increasing incorporation of immune checkpoint inhibitors (ICIs) in the first-line treatment of various cancers is an effective approach to counteract immunosuppressive factors within the tumor microenvironment (TME). Multiple clinical trials have commenced exploring the efficacy of checkpoint therapy in treating HPV-positive malignancies. A phase II clinical study investigating the combination of the PD-1 inhibitor nivolumab and the HPV16 peptide vaccine showed the efficacy of this combined immunotherapy, achieving an overall response rate of 33%, representing a significant improvement compared with the use of nivolumab or the HPV peptide vaccine alone.37 ISA101 is currently being investigated in combination with utomilumab (anti-4-1BB, NCT03258008) and cemiplimab (anti-PD1, NCT03669718). Additionally, ongoing studies are examining the combination therapy of VGX-3100 with anti-PDL1 treatment in a phase Ia/IIb clinical trial (NTC03162224). Claire et al. demonstrated that the combined treatment of PDS0101, the dual-function checkpoint inhibitor bintrafusp alfa, and the immune cytokine NHS-IL12 exhibited superior antitumor and immunostimulatory effects compared to monotherapies, resulting in elevated infiltration of CD8+ and CD4+ T cells into the TME.16 This study provides a theoretical basis for further preclinical and clinical investigations of combination therapies involving HPV therapeutic polypeptide vaccines with one or more immunomodulators.

In combination with other therapies

Marij et al. discovered that CarboTaxol chemotherapy does not suppress tumor-specific T- cells but instead exerts a potent stimulatory effect on tumor-specific immunity by restoring the abnormal quantity of immunosuppressive bone marrow cells. Furthermore, they extensively investigated the combined CarboTaxol and HPV16-SLP vaccine administration in a mouse model, yielding favorable therapeutic outcomes.38 A large-scale clinical trial (NCT02128126) has been initiated to explore the potential clinical benefits of this combined treatment approach in patients with advanced CC. Mariette et al. applied imiquimod, which is capable of inducing specific CD8+ T cell reactions to HPV16, at the vaccination site of ISA101. Although imiquimod did not improve vaccine efficacy, there was a rise in the intensity of specific T-cell immune responses. Their findings suggested a potential connection between the vaccine’s clinical efficacy and the magnitude of the immune response induced by it, as well as a link between clearance of vaccine-induced lesions and the immune response.39 The exploration of novel combination strategies for vaccines, such as the co-administration of emerging drugs or alternative therapeutic approaches to enhance the immune response to HPV therapeutic peptide vaccines, represents a potential direction for future research.

Conclusions

Significant progress has been made recently in the research and development of therapeutic HPV vaccines. Studies on HPV-related cancers or HPV-associated precancerous lesions have demonstrated that HPV therapeutic vaccines exhibit superior clinical efficacy, with higher median survival rates than conventional treatments. Peptide-based HPV therapeutic vaccines are stable, safe, and feasible for large-scale production; nevertheless, their immunogenicity is low. The progress of developing therapeutic peptide HPV vaccines has advanced primarily to the preclinical models and clinical trial stages, with limited progress toward formal application. In this study, it has been observed that addressing HLA-type restrictions enables the selection of safe and effective CTL epitope peptides tailored to diverse populations, thereby mitigating their low immunogenicity. In addition, appropriate adjuvants can augment the immune effects. The combination of ICIs with HPV therapeutic peptide-based vaccines has shown promising results in clinical trials. However, whether this can be established as a standard treatment strategy requires further investigation. Furthermore, altering delivery strategies using techniques such as PCI technology, nanoparticle delivery systems, and bacterial secretion vesicle delivery may enhance the efficacy of HPV therapeutic peptide vaccines. The co-administration of traditional Chinese medicine extracts and TLR receptor agonists as adjuvants, or the combination of CarboTaxol chemotherapy or imiquimod, has been shown to enhance the immune response generated by therapeutic peptide vaccines targeting HPV. Further investigations of the immunological mechanisms of HPV infection and its protein interactions, along with the creation of more appropriate peptide vaccines and combined therapeutic approaches tailored to individual cases, have the potential to greatly enhance the prognosis of patients with HPV-related cancers. Compared with traditional therapies, the combination of therapy and alterations in delivery strategies confer significant advantages and feasibility to HPV therapeutic peptide vaccines, with broad prospects for development. However, extensive clinical trials are required to validate their effectiveness.

Acknowledgments

We would like to thank Editage (www.editage.cn) for the English language editing.

Biographies

Rongyu Li is a graduate student majoring in Obstetrics and Gynecology at Sichuan University. His special interest include in Immunotherapy of ovarian cancer and the mechanism by which radiotherapy affects immunotherapy.

Xinlin He is a graduate student majoring in Obstetrics and Gynecology at Sichuan University. Her special interest include in Organoid orientation of ovarian cancer and HPV vaccine therapy.

Wanying Bao is a graduate student majoring in Obstetrics and Gynecology at Sichuan University. Her special interest include in the mechanism of development and targeted therapy of ovarian cancer.

Zhengyu Li MD, is the professor and deputy director of Obstetrics and Gynecology Department of West China Second Hospital of Sichuan University, an expert with outstanding contributions of the Sichuan Provincial Health and Family Planning Commission, and an academic and technical leader of the Sichuan Provincial Health and Family Planning Commission. He has won awards such as the Sichuan Provincial Youth Science and Technology Award and the First Prize of the Ministry of Education Science and Technology Progress Award, has authored (and coauthored) over 60 peer-reviewed scientific articles, and has extensive research experience in the fields of gynecological benign and malignant tumors and embryo implantation.

Funding Statement

This study was supported by the Medical Science and Technology Project of the Sichuan Provincial Health Commission [grant number: 2023NSFSC0743].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

R. L, X. H and W. B contributed to the manuscript preparation and writing; Z. L provided practical suggestions and critically revised the manuscript. All the authors contributed to the manuscript and approved the submitted version.

Data availability statement

All the data included in this study are available upon request from the corresponding authors.

References

• 1.Golia D’Augè T, Cuccu I, Etrusco A, D’Amato A, Laganà AS, D’Oria O, Bogani G, Di Donato V, Muzii L, Giannini A.. State of the art on hpv-related cervical lesions. Ital J Gynaecol Obstet. 2024;36(2):135. doi: 10.36129/jog.2024.161. [DOI] [Google Scholar]
• 2.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA a Cancer J Clinicians. 2018;68(6):394–7. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
• 3.Bogani G, Sopracordevole F, Ciavattini A, Ghelardi A, Vizza E, Vercellini P, Casarin J, Pinelli C, Ghezzi F, De Vincenzo R, et al. Hpv-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: a focus on the potential role of vaccination. Tumori J. 2024;110(2):139–145. doi: 10.1177/03008916231208344. [DOI] [PubMed] [Google Scholar]
• 4.Bhattacharjee R, Kumar L, Dhasmana A, Mitra T, Dey A, Malik S, Kim B, Gundamaraju R. Governing hpv-related carcinoma using vaccines: bottlenecks and breakthroughs. Front Oncol. 2022;12:12. doi: 10.3389/fonc.2022.977933. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 5.Chabeda A, Yanez RJR, Lamprecht R, Meyers AE, Rybicki EP, Hitzeroth II. Therapeutic vaccines for high-risk hpv-associated diseases. Papillomavirus Res. 2018;5:46–58. doi: 10.1016/j.pvr.2017.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 6.Rosales R, López-Contreras M, Rosales C, Magallanes-Molina J-R, Gonzalez-Vergara R, Arroyo-Cazarez JM, Ricardez-Arenas A, Del Follo-Valencia A, Padilla-Arriaga S, Guerrero MV, et al. Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine. Hum Gene Ther. 2014;25(12):1035–1049. doi: 10.1089/hum.2014.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 7.Tang J, Li M, Zhao C, Shen D, Liu L, Zhang X, Wei L. Therapeutic DNA vaccines against HPV-Related malignancies: promising leads from clinical trials. Viruses. 2022;14(2):14. doi: 10.3390/v14020239. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 8.Mariz FC, Balz K, Dittrich M, Zhang Y, Yang F, Zhao X, Bolchi A, Ottonello S, Müller M. A broadly protective vaccine against cutaneous human papillomaviruses. npj Vaccines. 2022;7(1). doi: 10.1038/s41541-022-00539-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 9.Feng F, Wen Z, Chen J, Yuan Y, Wang C, Sun C. Strategies to develop a mucosa-targeting vaccine against emerging infectious diseases. Viruses. 2022;14(3):14. doi: 10.3390/v14030520. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 10.van der Burg SH, Ressing ME, Kwappenberg KMC, de Jong A, Straathof K, de Jong J, Geluk A, van Meijgaarden KE, Franken KLMC, Ottenhoff THM, et al. Natural T-helper immunity against human papillomavirus type 16 (hpv16) e7-derived peptide epitopes in patients with hpv16-positive cervical lesions: identification of 3 human leukocyte antigen class ii-restricted epitopes. Int J Cancer. 2001;91(5):612–618. doi: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1119>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
• 11.Alexander J, Sidney J, Southwood S, Ruppert J, Oseroff C, Maewal A, Snoke K, Serra HM, Kubo RT, Sette A, et al. Development of high potency universal dr-restricted helper epitopes by modification of high affinity dr-blocking peptides. Immunity. 1994;1(9):751–761. doi: 10.1016/S1074-7613(94)80017-0. [DOI] [PubMed] [Google Scholar]
• 12.Greenfield WW, Stratton SL, Myrick RS, Vaughn R, Donnalley LM, Coleman HN, Mercado M, Moerman-Herzog AM, Spencer HJ, Andrews-Collins NR, et al. A phase I dose-escalation clinical trial of a peptide-based human papillomavirus therapeutic vaccine with Candida skin test reagent as a novel vaccine adjuvant for treating women with biopsy-proven cervical intraepithelial neoplasia 2/3. OncoImmunol. 2015;4(10):4. doi: 10.1080/2162402X.2015.1031439. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 13.van Poelgeest MIE, Welters MJP, van Esch EMG, Stynenbosch LFM, Kerpershoek G, van Persijn van Meerten EL, van den Hende M, Löwik MJG, Berends-van der Meer DMA, Fathers LM, et al. HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial. J Transl Med. 2013;11(1):11. doi: 10.1186/1479-5876-11-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 14.de Vos van Steenwijk PJ, van Poelgeest MIE, Ramwadhdoebe TH, Löwik MJG, Berends-van der Meer DMA, van der Minne CE, Loof NM, Stynenbosch LFM, Fathers LM, Valentijn ARPM, et al. The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study. Cancer Immunol Immunother. 2014;63(2):147–160. doi: 10.1007/s00262-013-1499-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 15.Zandberg DP, Rollins S, Goloubeva O, Morales RE, Tan M, Taylor R, Wolf JS, Schumaker LM, Cullen KJ, Zimrin A, et al. A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). Cancer Immunol Immunother. 2015;64(3):367–379. doi: 10.1007/s00262-014-1640-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 16.Smalley Rumfield C, Pellom ST, Morillon Ii YM, Schlom J, Jochems C. Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine. J Immunother Cancer. 2020;8(1):8. doi: 10.1136/jitc-2020-000612. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 17.Karkada M, Quinton T, Blackman R, Mansour M. Tumor inhibition by DepoVax-based cancer vaccine is accompanied by reduced regulatory/suppressor cell proliferation and tumor infiltration. ISRN Oncol. 2013;2013:1–13. doi: 10.1155/2013/753427. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 18.Barnett C, Joubert F, Iliopoulou A, Álvarez RS, Pasparakis G. Photochemical internalization using natural anticancer drugs, antimetabolites, and Nanoformulations: a systematic study against breast and pancreatic cancer cell lines. Mol Pharm. 2023;20(3):1818–1841. doi: 10.1021/acs.molpharmaceut.2c01012. [DOI] [PubMed] [Google Scholar]
• 19.Haug M, Brede G, Håkerud M, Nedberg AG, Gederaas OA, Flo TH, Edwards VT, Selbo PK, Høgset A, Halaas Ø. Photochemical internalization of peptide antigens provides a novel strategy to realize therapeutic cancer vaccination. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.00650. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 20.Otterhaug T, Janetzki S, Welters MJP, Håkerud M, Nedberg AG, Edwards VT, Boekestijn S, Loof NM, Selbo PK, Olivecrona H, et al. Photochemical internalization enhanced vaccination is safe, and gives promising cellular immune responses to an HPV peptide-based vaccine in a phase I clinical study in healthy volunteers. Front Immunol. 2021;11:11. doi: 10.3389/fimmu.2020.576756. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 21.Xiang SD, Wilson KL, Goubier A, Heyerick A, Plebanski M. Design of peptide-based nanovaccines targeting leading antigens from gynecological cancers to induce HLA-A2.1 restricted CD8+ T cell responses. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.02968. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 22.Zhao G, Chandrudu S, Skwarczynski M, Toth I. The application of self-assembled nanostructures in peptide-based subunit vaccine development. Eur Polym J. 2017;93:670–681. doi: 10.1016/j.eurpolymj.2017.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 23.Chen H, Zheng X, Li L, Huang L, Huang W, Ma Y. Peptide-based therapeutic HPV cancer vaccine synthesized via bacterial outer membrane vesicles. Int J Nanomed. 2023;18:4541–4554. doi: 10.2147/IJN.S416706. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 24.Chen M-H, Li W-S, Lue Y-S, Chu C-L, Pan IH, Ko C-H, Chen D-Y, Lin C-H, Lin S-H, Chang C-P, et al. Clitocybe nudaActivates dendritic cells and acts as a DNA vaccine adjuvant. Evidence-Based Complementary Alternative Med. 2013;2013:1–15. doi: 10.1155/2013/761454. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 25.Du X, Zhao B, Li J, Cao X, Diao M, Feng H, Chen X, Chen Z, Zeng X. Astragalus polysaccharides enhance immune responses of HBV DNA vaccination via promoting the dendritic cell maturation and suppressing treg frequency in mice. Int Immunopharmacol. 2012;14(4):463–470. doi: 10.1016/j.intimp.2012.09.006. [DOI] [PubMed] [Google Scholar]
• 26.Zhao X, Lu Y, Tao Y, Huang Y, Wang D, Hu Y, Liu J, Wu Y, Yu Y, Liu C, et al. Salidroside liposome formulation enhances the activity of dendritic cells and immune responses. Int Immunopharmacol. 2013;17(4):1134–1140. doi: 10.1016/j.intimp.2013.10.016. [DOI] [PubMed] [Google Scholar]
• 27.Chang J-M, Hung L-M, Chyan Y-J, Cheng C-M, Wu R-Y. Carthamus tinctorius enhances the antitumor activity of dendritic cell vaccines via polarization toward Th1 cytokines and increase of cytotoxic T lymphocytes. Evidence-Based Complement Alternative Med. 2011;2011(1):1–10. doi: 10.1093/ecam/nen068. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 28.Song Y-C, Huang H-C, Chang C-Y, Lee H-J, Liu C-T, Lo H-Y, Ho T-Y, Lin W-C, Yen H-R. A potential herbal adjuvant combined with a peptide-based vaccine acts against HPV-Related tumors through enhancing effector and memory T-Cell immune responses. Front Immunol. 2020;11:11. doi: 10.3389/fimmu.2020.00062. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 29.Reed SG, Hsu F-C, Carter D, Orr MT. The science of vaccine adjuvants: advances in TLR4 ligand adjuvants. Curr Opin In Immunol. 2016;41:85–90. doi: 10.1016/j.coi.2016.06.007. [DOI] [PubMed] [Google Scholar]
• 30.Jiménez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like receptors — from microbial recognition to autoimmunity: a comprehensive review. Autoimmunity Rev. 2016;15(1):1–8. doi: 10.1016/j.autrev.2015.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 31.Giannini S, Hanon E, Moris P, Vanmechelen M, Morel S, Dessy F, Fourneau M, Colau B, Suzich J, Losonksy G, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine. 2006;24(33–34):5937–5949. doi: 10.1016/j.vaccine.2006.06.005. [DOI] [PubMed] [Google Scholar]
• 32.Fox CB, Friede M, Reed SG, Ireton GC. Synthetic and natural TLR4 agonists as safe and effective vaccine adjuvants. Subcell Biochem. 2010;53:303–321. doi: 10.1007/978-90-481-9078-2_14. [DOI] [PubMed] [Google Scholar]
• 33.Johnson DA. TLR4 agonists as vaccine adjuvants: a chemist’s perspective. Expert Rev Vaccines. 2013;12(7):711–713. doi: 10.1586/14760584.2013.811189. [DOI] [PubMed] [Google Scholar]
• 34.Yazdani Z, Rafiei A, Valadan R, Ashrafi H, Pasandi M, Kardan M. Designing a potent L1 protein-based HPV peptide vaccine: a bioinformatics approach. Comput Biol Chem. 2020;85:107209. doi: 10.1016/j.compbiolchem.2020.107209. [DOI] [PubMed] [Google Scholar]
• 35.Speetjens FM, Welters MJP, Slingerland M, van Poelgeest MIE, de Vos van Steenwijk PJ, Roozen I, Boekestijn S, Loof NM, Zom GG, Valentijn ARPM, et al. Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions. J Immunother Cancer. 2022;10(10):e005016. doi: 10.1136/jitc-2022-005016. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 36.Wu C-Y, Monie A, Pang X, Hung C-F, Wu TC. Improving therapeutic HPV peptide-based vaccine potency by enhancing CD4+ T help and dendritic cell activation. J Biomed Sci. 2010;17(1):17. doi: 10.1186/1423-0127-17-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 37.Massarelli E, William W, Johnson F, Kies M, Ferrarotto R, Guo M, Feng L, Lee JJ, Tran H, Kim YU, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16–related cancer. JAMA Oncol. 2019;5(1):67. doi: 10.1001/jamaoncol.2018.4051. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 38.Welters MJ, van der Sluis TC, van Meir H, Loof NM, van Ham VJ, van Duikeren S, Santegoets SJ, Arens R, de Kam ML, Cohen AF, et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci Transl Med. 2016;8(334). doi: 10.1126/scitranslmed.aad8307. [DOI] [PubMed] [Google Scholar]
• 39.van Poelgeest MIE, Welters MJP, Vermeij R, Stynenbosch LFM, Loof NM, Berends-van der Meer DMA, Löwik MJG, Hamming ILE, van Esch EMG, Hellebrekers BWJ, et al. Vaccination against oncoproteins of HPV16 for noninvasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-Cell response. Clin Cancer Res. 2016;22(10):2342–2350. doi: 10.1158/1078-0432.CCR-15-2594. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All the data included in this study are available upon request from the corresponding authors.