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Josi R, Speiser DE, de Brot S, Vogt AC, Sevick-Muraca EM, Tolstonog GV, Bachmann MF, Mohsen MO. A tetravalent nanovaccine that inhibits growth of HPV-associated head and neck carcinoma via dendritic and T cell activation. iScience 2024; 27:109439. [PMID: 38523774 PMCID: PMC10957412 DOI: 10.1016/j.isci.2024.109439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 12/17/2023] [Accepted: 03/04/2024] [Indexed: 03/26/2024] Open
Abstract
The global incidence of human papillomavirus (HPV) associated head and neck carcinoma is on the rise, in response to this a tetravalent therapeutic vaccine named Qβ-HPVag was developed. This vaccine, utilizing virus-like particles (VLPs) loaded with toll-like receptor ligands and chemically coupled to four HPV16-derived peptides, demonstrated strong anti-tumor effects in a murine head and neck cancer model. Qβ-HPVag impeded tumor progression, increased infiltration of HPV-specific T cells, and significantly improved survival. The vaccine`s efficacy was associated with immune repolarization in the tumor microenvironment, characterized by expanded activated dendritic cell subsets (cDC1, cDC2, DC3). Notably, mice responding to treatment exhibited a higher percentage of migratory DC3 cells expressing CCR7. These findings suggest promising prospects for optimized VLP-based vaccines in treating HPV-associated head and neck cancer.
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Affiliation(s)
- Romano Josi
- Department of Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), Bern, Switzerland
| | - Daniel E. Speiser
- Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Simone de Brot
- COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland
| | - Anne-Cathrine Vogt
- Department of Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), Bern, Switzerland
| | - Eva M. Sevick-Muraca
- Center for Molecular Imaging, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Genrich V. Tolstonog
- Department of Otolaryngology – Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Agora Cancer Research Centre, Lausanne, Switzerland
| | - Martin F. Bachmann
- Department of Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Nuffield Department of Medicine, The Henry Welcome Building for Molecular Physiology, The Jenner Institute, University of Oxford, Oxford, UK
| | - Mona O. Mohsen
- Department of Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland
- Department of BioMedical Research, University of Bern, Bern, Switzerland
- Tajarub Research & Development, Doha, State of Qatar
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Alouini S, Pichon C. Therapeutic Vaccines for HPV-Associated Cervical Malignancies: A Systematic Review. Vaccines (Basel) 2024; 12:428. [PMID: 38675811 PMCID: PMC11054545 DOI: 10.3390/vaccines12040428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/07/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
IMPORTANCE Despite widespread prophylactic vaccination, cervical cancer continues to be a major health problem with considerable mortality. Currently, therapeutic vaccines for HPV-associated cervical malignancies are being evaluated as a potential complement to the standard treatment. OBJECTIVE The present systematic review was conducted on randomized controlled trials (RCTs) to investigate the effects of therapeutic vaccines on the treatment of patients with cervical cancer and cervical intraepithelial neoplasia (CIN) of Grades 2 and 3. EVIDENCE REVIEW The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched. Only articles in English published up until 31 January 2024 were selected. Also, reference lists of the selected original papers and recent review articles were manually searched for additional sources. Data on study characteristics were extracted from the selected articles. Data on outcomes of interest were synthesized, and vaccine efficacy endpoints (histological lesion regression, clinical response, and overall survival) were selected as the basis for grouping the studies. FINDINGS After screening 831 articles, nine RCTs with 800 participants were included, of which seven studies with 677 participants involved CIN2 and CIN3 and examined lesion regression to ≤CIN1 as the efficacy endpoint. Results of two of these studies were deemed to have a high risk of bias, and another one did not contain statistical analyses. Results of the other four studies were quantitively synthesized, and the pooling of p-values revealed a significant difference between the vaccine and placebo groups in terms of lesion regression (p-values of 0.135, 0.049, and 0.034 in RCTs, yielding a combined p-value of 0.010). The certainty of the evidence was rated as moderate. Patients with advanced cervical cancers were studied in two RCTs with 123 participants. Clinical response and overall survival were taken as endpoints, and the results were reported as not significant. The certainty of the evidence of these results was rated as very low, mainly due to the very small number of events. All studies reported good tolerance for the vaccines. CONCLUSIONS AND RELEVANCE The results indicate the potential for therapeutic vaccines in the regression of CIN2 and CIN3 lesions. Moreover, a potential gap in evidence is identified regarding the very low number of RCTs in patients with advanced cervical cancer.
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Affiliation(s)
- Souhail Alouini
- Departement of Gynecological Surgery, Centre Hospitalier Universitaire d’Orléans, 14 Avenue de l’Hôpital, 45100 Orleans, France
- Faculté de Médecine, Université d’Orléans, 45100 Orleans, France
| | - Chantal Pichon
- Institut Universitaire de France, 1 rue Descartes, 75035 Paris, France;
- INSERM ART ARNm, University of Orléans, 45100 Orleans, France
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Gonçalves CA, Pereira-da-Silva G, Silveira RCCP, Mayer PCM, Zilly A, Lopes-Júnior LC. Safety, Efficacy, and Immunogenicity of Therapeutic Vaccines for Patients with High-Grade Cervical Intraepithelial Neoplasia (CIN 2/3) Associated with Human Papillomavirus: A Systematic Review. Cancers (Basel) 2024; 16:672. [PMID: 38339423 PMCID: PMC10854525 DOI: 10.3390/cancers16030672] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/26/2023] [Accepted: 10/12/2023] [Indexed: 02/12/2024] Open
Abstract
Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT.
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Affiliation(s)
- Caroline Amélia Gonçalves
- Maternal-Infant and Public Health Nursing Department, University of São Paulo at Ribeirão Preto School of Nursing, Campus Ribeirão Preto, Ribeirão Preto 14040-902, Brazil; (C.A.G.)
| | - Gabriela Pereira-da-Silva
- Maternal-Infant and Public Health Nursing Department, University of São Paulo at Ribeirão Preto School of Nursing, Campus Ribeirão Preto, Ribeirão Preto 14040-902, Brazil; (C.A.G.)
| | - Renata Cristina Campos Pereira Silveira
- Maternal-Infant and Public Health Nursing Department, University of São Paulo at Ribeirão Preto School of Nursing, Campus Ribeirão Preto, Ribeirão Preto 14040-902, Brazil; (C.A.G.)
| | | | - Adriana Zilly
- Center for Education, Literature and Health, State University of West of Parana, Cascavel 85819-110, Brazil
| | - Luís Carlos Lopes-Júnior
- Health Sciences Center, Universidade Federal do Espirito Santo (UFES), Av. Marechal Campos, 1468—Maruípe, Vitoria 29043-900, Brazil
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Kobayashi O, Taguchi A, Nakajima T, Ikeda Y, Saito K, Kawana K. Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer. Taiwan J Obstet Gynecol 2024; 63:22-28. [PMID: 38216264 DOI: 10.1016/j.tjog.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 01/14/2024] Open
Abstract
Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.
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Affiliation(s)
- Osamu Kobayashi
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Takahiro Nakajima
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Keisuke Saito
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Nihon University School of Medicine, Japan.
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Ibrahim Khalil A, Zhang L, Muwonge R, Sauvaget C, Basu P. Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions: a systematic review and meta-analysis of phase II/III clinical trials. BMJ Open 2023; 13:e069616. [PMID: 37879679 PMCID: PMC10603536 DOI: 10.1136/bmjopen-2022-069616] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 10/09/2023] [Indexed: 10/27/2023] Open
Abstract
OBJECTIVES We aim to assess the efficacy and safety of therapeutic human papillomavirus (HPV) vaccines to treat cervical intraepithelial neoplasia of grade 2 or 3 (CIN 2/3). DESIGN Systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. DATA SOURCES PubMed, Embase, Web of Science, Global Index Medicus and CENTRAL Cochrane were searched up to 31 January 2022. ELIGIBILITY CRITERIA Phase II/III randomised controlled trials (RCTs) and single-arm studies reporting the efficacy of therapeutic vaccines to achieve regression of CIN 2/3 lesions were included. Studies evaluating only safety and side effects of the vaccine were excluded. DATA EXTRACTION AND SYNTHESIS Two independent reviewers extracted data and evaluated study quality. A random-effect model was used to pool the proportions of regression and/or HPV clearance. RESULTS 12 trials met the inclusion criteria. Out of 734 women (all studies considered) receiving therapeutic HPV vaccine for CIN 2/3, 414 regressed to normal/CIN 1 with an overall proportion of regression of 0.54 (95% CI 0.39 to 0.69) for vaccinated group; 166 women (from five RCTs) receiving placebo only achieving a pooled normal/CIN 1 regression of 0.27 (95% CI 0.20 to 0.34). When including only the five two-arm studies, the regression proportion for the 410 vaccine group participants was higher than that of the 166 control group participants (relative risk (RR) 1.52; 95% CI 1.14 to 2.04). The pooled proportion of high-risk human papillomavirus (hrHPV) clearance was 0.42 (95% CI 0.32 to 0.52) in the vaccine group (six studies with a total of 357 participants) and 0.17 (95% CI 0.11 to 0.26) in the control group (three RCTs with a total of 104 participants). Based on these three RCTs, the hrHPV clearance was significantly higher in the vaccinated group (250 participants) compared with the control group (RR 2.03; 95% CI 1.30 to 3.16). Similar results were found regarding HPV 16/18 clearance. No significant unsolicited adverse events have been consistently reported. CONCLUSIONS The efficacy of the therapeutic vaccines in the treatment of CIN 2/3 was modest. Implementation issues such as feasibility, acceptability, adoption and cost-effectiveness need to be further studied. PROSPERO REGISTRATION NUMBER CRD42022307418.
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Affiliation(s)
| | - Li Zhang
- International Agency for Research on Cancer, Lyon, Rhône-Alpes, France
| | - Richard Muwonge
- International Agency for Research on Cancer, Lyon, Rhône-Alpes, France
| | | | - Partha Basu
- International Agency for Research on Cancer, Lyon, Rhône-Alpes, France
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Mellid-Carballal R, Gutierrez-Gutierrez S, Rivas C, Garcia-Fuentes M. Viral protein-based nanoparticles (part 2): Pharmaceutical applications. Eur J Pharm Sci 2023; 189:106558. [PMID: 37567394 DOI: 10.1016/j.ejps.2023.106558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 07/10/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023]
Abstract
Viral protein nanoparticles (ViP NPs) such as virus-like particles and virosomes are structures halfway between viruses and synthetic nanoparticles. The biological nature of ViP NPs endows them with the biocompatibility, biodegradability, and functional properties that many synthetic nanoparticles lack. At the same time, the absence of a viral genome avoids the safety concerns of viruses. Such characteristics of ViP NPs offer a myriad of opportunities for theirapplication at several points across disease development: from prophylaxis to diagnosis and treatment. ViP NPs present remarkable immunostimulant properties, and thus the vaccination field has benefited the most from these platforms capable of overcoming the limitations of both traditional and subunit vaccines. This was reflected in the marketing authorization of several VLP- and virosome-based vaccines. Besides, ViP NPs inherit the ability of viruses to deliver their cargo to target cells. Because of that, ViP NPs are promising candidates as vectors for drug and gene delivery, and for diagnostic applications. In this review, we analyze the pharmaceutical applications of ViP NPs, describing the products that are commercially available or under clinical evaluation, but also the advances that scientists are making toward the implementation of ViP NPs in other areas of major pharmaceutical interest.
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Affiliation(s)
- Rocio Mellid-Carballal
- CiMUS Research Center, Universidad de Santiago de Compostela, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Universidad de Santiago de Compostela, Spain
| | - Sara Gutierrez-Gutierrez
- CiMUS Research Center, Universidad de Santiago de Compostela, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Universidad de Santiago de Compostela, Spain
| | - Carmen Rivas
- CiMUS Research Center, Universidad de Santiago de Compostela, Spain; Health Research Institute of Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, Spain; Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CNB)-CSIC, Spain
| | - Marcos Garcia-Fuentes
- CiMUS Research Center, Universidad de Santiago de Compostela, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Universidad de Santiago de Compostela, Spain; Health Research Institute of Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, Spain.
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7
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Boisen M, Guido R. Emerging Treatment Options for Cervical Dysplasia and Early Cervical Cancer. Clin Obstet Gynecol 2023; 66:500-515. [PMID: 37650664 DOI: 10.1097/grf.0000000000000790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
DISCUSSION of treatment strategies for cervical cancer precursors, review of medical therapies and emerging therapeutics for treatment of cervical cancers, and updates on new approaches to treating early-stage cervical cancers.
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Affiliation(s)
- Michelle Boisen
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania
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8
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Yan F, Cowell LG, Tomkies A, Day AT. Therapeutic Vaccination for HPV-Mediated Cancers. CURRENT OTORHINOLARYNGOLOGY REPORTS 2023; 11:44-61. [PMID: 36743978 PMCID: PMC9890440 DOI: 10.1007/s40136-023-00443-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2022] [Indexed: 02/04/2023]
Abstract
Purpose of Review The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers. Recent Findings Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise. Summary Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.
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Affiliation(s)
- Flora Yan
- Department of Otolaryngology-Head and Neck Surgery, Temple University, Philadelphia, PA USA
| | - Lindsay G Cowell
- Peter O'Donnell Jr. School of Public Health, Department of Immunology, UT Southwestern Medical Center, Dallas, TX USA
| | - Anna Tomkies
- Department of Otolaryngology-Head and Neck Surgery, UT Southwestern Medical Center, 2001 Inwood Blvd, Dallas, TX 75390-9035 USA
| | - Andrew T Day
- Department of Otolaryngology-Head and Neck Surgery, UT Southwestern Medical Center, 2001 Inwood Blvd, Dallas, TX 75390-9035 USA
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Ventura C, Luís Â, Soares CP, Venuti A, Paolini F, Pereira L, Sousa Â. The Effectiveness of Therapeutic Vaccines for the Treatment of Cervical Intraepithelial Neoplasia 3: A Systematic Review and Meta-Analysis. Vaccines (Basel) 2022; 10:vaccines10091560. [PMID: 36146638 PMCID: PMC9500864 DOI: 10.3390/vaccines10091560] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 11/19/2022] Open
Abstract
Cervical cancer (CC) is a disease that affects many women worldwide, especially in low-income countries. The human papilloma virus (HPV) is the main causative agent of this disease, with the E6 and E7 oncoproteins being responsible for the development and maintenance of transformed status. In addition, HPV is also responsible for the appearance of cervical intraepithelial neoplasia (CIN), a pre-neoplastic condition burdened by very high costs for its screening and therapy. So far, only prophylactic vaccines have been approved by regulatory agencies as a means of CC prevention. However, these vaccines cannot treat HPV-positive women. A search was conducted in several databases (PubMed, Scopus, Web of Science, and ClinicalTrials.gov) to systematically identify clinical trials involving therapeutic vaccines against CIN 3. Histopathological regression data, immunological parameters, safety, DNA clearance, and vaccine efficacy were considered from each selected study, and from the 102 articles found, 8 were selected based on the defined inclusion criteria. Histopathological regression from CIN 3 to CIN < 1 was 22.1% (95% CI: 0.627−0.967; p-value = 0.024), showing a vaccine efficacy of 23.6% (95% CI; 0.666−0.876; p-value < 0.001). DNA clearance was assessed, and the risk of persistent HPV DNA was 23.2% (95% CI: 0.667−0.885; p-value < 0.001). Regarding immunological parameters, immune responses by specific T-HPV cells were more likely in vaccinated women (95% CI: 1.245−9.162; p-value = 0.017). In short, these studies favored the vaccine group over the placebo group. This work indicated that therapeutic vaccines are efficient in the treatment of CIN 3, even after accounting for publication bias.
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Affiliation(s)
- Cathy Ventura
- CICS-UBI–Health Science Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
| | - Ângelo Luís
- CICS-UBI–Health Science Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
- Grupo de Revisões Sistemáticas (GRUBI), Faculdade de Ciências da Saúde, Universidade da Beira Interior, 6200-506 Covilhã, Portugal
| | - Christiane P. Soares
- Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Campus Ville, Araraquara 14800-903, SP, Brazil
| | - Aldo Venuti
- HPV-UNIT-UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Francesca Paolini
- HPV-UNIT-UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Luísa Pereira
- Grupo de Revisões Sistemáticas (GRUBI), Faculdade de Ciências da Saúde, Universidade da Beira Interior, 6200-506 Covilhã, Portugal
- CMA-UBI-Centro de Matemática e Aplicações, Universidade da Beira Interior, 6200-001 Covilhã, Portugal
- C4-UBI, Cloud Computing Competence Centre, University of Beira Interior, 6200-284 Covilhã, Portugal
- Correspondence: (L.P.); (Â.S.); Tel.: +351-275-329-052 (L.P. & Â.S.)
| | - Ângela Sousa
- CICS-UBI–Health Science Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
- Correspondence: (L.P.); (Â.S.); Tel.: +351-275-329-052 (L.P. & Â.S.)
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10
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Cai S, Tan X, Miao K, Li D, Cheng S, Li P, Zeng X, Sun F. Effectiveness and Safety of Therapeutic Vaccines for Precancerous Cervical Lesions: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:918331. [PMID: 35734598 PMCID: PMC9207463 DOI: 10.3389/fonc.2022.918331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Objective This study systematically evaluated the effectiveness and safety of therapeutic vaccines for precancerous cervical lesions, providing evidence for future research. Methods We systematically searched the literature in 10 databases from inception to February 18, 2021. Studies on the effectiveness and safety of therapeutic vaccines for precancerous cervical lesions were included. Then, we calculated the overall incidence rates of four outcomes, for which we used the risk ratio (RR) and 95% confidence interval (95% CI) to describe the effects of high-grade squamous intraepithelial lesions (HSILs) on recurrence. Results A total of 39 studies were included, all reported in English, published from 1989 to 2021 in 16 countries. The studies covered 22,865 women aged 15-65 years, with a total of 5,794 vaccinated, and 21 vaccines were divided into six types. Meta-analysis showed that the overall incidence rate of HSIL regression in vaccine therapies was 62.48% [95% CI (42.80, 80.41)], with the highest rate being 72.32% for viral vector vaccines [95% CI (29.33, 99.51)]. Similarly, the overall incidence rates of HPV and HPV16/18 clearance by vaccines were 48.59% [95% CI (32.68, 64.64)] and 47.37% [95% CI (38.00, 56.81)], respectively, with the highest rates being 68.18% [95% CI (45.13, 86.14)] for bacterial vector vaccines and 55.14% [95% CI (42.31, 67.66)] for DNA-based vaccines. In addition, a comprehensive analysis indicated that virus-like particle vaccines after conization reduced the risk of HSIL recurrence with statistical significance compared to conization alone [RR = 0.46; 95% CI (0.29, 0.74)]. Regarding safety, only four studies reported a few severe adverse events, indicating that vaccines for precancerous cervical lesions are generally safe. Conclusion Virus-like particle vaccines as an adjuvant immunotherapy for conization can significantly reduce the risk of HSIL recurrence. Most therapeutic vaccines have direct therapeutic effects on precancerous lesions, and the effectiveness in HSIL regression, clearance of HPV, and clearance of HPV16/18 is great with good safety. That is, therapeutic vaccines have good development potential and are worthy of further research. Systematic Review Registration PROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021275452.
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Affiliation(s)
- Shan Cai
- Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China
| | - Xiaoyu Tan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Ke Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Dantong Li
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing, China
| | - Si Cheng
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Pei Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Xueyang Zeng
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Feng Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
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Muntinga CLP, de Vos van Steenwijk PJ, Bekkers RLM, van Esch EMG. Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy. J Clin Med 2022; 11:jcm11051432. [PMID: 35268523 PMCID: PMC8910829 DOI: 10.3390/jcm11051432] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/10/2022] Open
Abstract
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs.
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Affiliation(s)
- Caroline L. P. Muntinga
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Peggy J. de Vos van Steenwijk
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
- Department of Gynecology and Obstetrics, Maastricht Universitair Medisch Centrum, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Ruud L. M. Bekkers
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Edith M. G. van Esch
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- Correspondence: ; Tel.: +31-402-399-111
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12
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Hillebrandt N, Vormittag P, Dietrich A, Hubbuch J. Process Monitoring Framework for Cross‐flow Diafiltration‐based Virus‐like Particle Disassembly: Tracing Product Properties and Filtration Performance. Biotechnol Bioeng 2022; 119:1522-1538. [DOI: 10.1002/bit.28063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Nils Hillebrandt
- Institute of Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe Institute of Technology (KIT) Fritz‐Haber‐Weg 2 76131 Karlsruhe Baden‐Württemberg Germany
| | - Philipp Vormittag
- Institute of Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe Institute of Technology (KIT) Fritz‐Haber‐Weg 2 76131 Karlsruhe Baden‐Württemberg Germany
| | - Annabelle Dietrich
- Institute of Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe Institute of Technology (KIT) Fritz‐Haber‐Weg 2 76131 Karlsruhe Baden‐Württemberg Germany
| | - Jürgen Hubbuch
- Institute of Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe Institute of Technology (KIT) Fritz‐Haber‐Weg 2 76131 Karlsruhe Baden‐Württemberg Germany
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13
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Zhang J, Fan J, Skwarczynski M, Stephenson RJ, Toth I, Hussein WM. Peptide-Based Nanovaccines in the Treatment of Cervical Cancer: A Review of Recent Advances. Int J Nanomedicine 2022; 17:869-900. [PMID: 35241913 PMCID: PMC8887913 DOI: 10.2147/ijn.s269986] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/09/2022] [Indexed: 12/24/2022] Open
Abstract
Persistent infection with high-risk human papillomaviruses (HPVs), such as HPV-16 and HPV-18, can induce cervical cancer in humans. The disease carries high morbidity and mortality among females worldwide. Inoculation with prophylactic HPV vaccines, such as Gardasil® or Cervarix®, is the predominant method of preventing cervical cancer in females 6 to 26 years of age. However, despite the availability of commercial prophylactic HPV vaccines, no therapeutic HPV vaccines to eliminate existing HPV infections have been approved. Peptide-based vaccines, which form one of the most potent vaccine platforms, have been broadly investigated to overcome this shortcoming. Peptide-based vaccines are especially effective in inducing cellular immune responses and eradicating tumor cells when combined with nanoscale adjuvant particles and delivery systems. This review summarizes progress in the development of peptide-based nanovaccines against HPV infection.
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Affiliation(s)
- Jiahui Zhang
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Jingyi Fan
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Mariusz Skwarczynski
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Rachel J Stephenson
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Istvan Toth
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia
- Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Waleed M Hussein
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
- Correspondence: Waleed M Hussein, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia, Tel +61 7 3365 2782, Email
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14
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Höpfl R. Von Kaninchenhörnern zur HPV‐Krebsimpfung, die Mission ist noch nicht erfüllt! J Dtsch Dermatol Ges 2020; 18:1345-1346. [DOI: 10.1111/ddg.14237_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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15
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Zhao X, Yang F, Mariz F, Osen W, Bolchi A, Ottonello S, Müller M. Combined prophylactic and therapeutic immune responses against human papillomaviruses induced by a thioredoxin-based L2-E7 nanoparticle vaccine. PLoS Pathog 2020; 16:e1008827. [PMID: 32886721 PMCID: PMC7498061 DOI: 10.1371/journal.ppat.1008827] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/17/2020] [Accepted: 07/21/2020] [Indexed: 01/08/2023] Open
Abstract
Global burden of cervical cancer, the most common cause of mortality caused by human papillomavirus (HPV), is expected to increase during the next decade, mainly because current alternatives for HPV vaccination and cervical cancer screening programs are costly to be established in low-and-middle income countries. Recently, we described the development of the broadly protective, thermostable vaccine antigen Trx-8mer-OVX313 based on the insertion of eight different minor capsid protein L2 neutralization epitopes into a thioredoxin scaffold from the hyperthermophilic archaeon Pyrococcus furiosus and conversion of the resulting antigen into a nanoparticle format (median radius ~9 nm) upon fusion with the heptamerizing OVX313 module. Here we evaluated whether the engineered thioredoxin scaffold, in addition to humoral immune responses, can induce CD8+ T-cell responses upon incorporation of MHC-I-restricted epitopes. By systematically examining the contribution of individual antigen modules, we demonstrated that B-cell and T-cell epitopes can be combined into a single antigen construct without compromising either immunogenicity. While CD8+ T-cell epitopes had no influence on B-cell responses, the L2 polytope (8mer) and OVX313-mediated heptamerization of the final antigen significantly increased CD8+ T-cell responses. In a proof-of-concept experiment, we found that vaccinated mice remained tumor-free even after two consecutive tumor challenges, while unvaccinated mice developed tumors. A cost-effective, broadly protective vaccine with both prophylactic and therapeutic properties represents a promising option to overcome the challenges associated with prevention and treatment of HPV-caused diseases. Currently, there are three licensed prophylactic vaccines available against HPV, but none of them shows a therapeutic effect on pre-existing infections. Thus, a prophylactic vaccine also endowed with a therapeutic activity presents application potentials to individuals regardless of their HPV-infection status. Such a dual-purpose vaccine would be particularly valuable for post-exposure prophylaxis and shields population from recurrent HPV infections. Here, we constructed a combined vaccine relying on L2- and E7-specific epitopes grafted onto the surface of a hyper-stable thioredoxin scaffold. The resulting antigen was converted into a nanoparticle format with the use of a heptamerization domain. Our data document that the modular design of the antigen allows combination of B-cell and T-cell epitopes in one antigen without compromising either’s immunogenicity. The antigen retains its ability to provide broad protection against different HPV types but also presents strong therapeutic effects in a mouse tumor model. Therefore, the vaccine is potentially capable of resolving productive infection as well as HPV-related malignancies, and thus benefitting both uninfected and already infected individuals. Moreover, our vaccine utilizes E. coli as protein producer and distribution does not require cold-chain, which reduces costs making it applicable to less-affluent countries.
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MESH Headings
- Animals
- Antigens, Neoplasm/chemistry
- Antigens, Neoplasm/pharmacology
- Antigens, Viral/chemistry
- Antigens, Viral/pharmacology
- Archaeal Proteins/chemistry
- Archaeal Proteins/pharmacology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/pathology
- Cancer Vaccines/chemistry
- Cancer Vaccines/pharmacology
- Epitopes, B-Lymphocyte/chemistry
- Epitopes, B-Lymphocyte/pharmacology
- Epitopes, T-Lymphocyte/chemistry
- Epitopes, T-Lymphocyte/pharmacology
- Female
- Humans
- Immunity, Cellular/drug effects
- Mice
- Mice, Inbred BALB C
- Nanoparticles/chemistry
- Nanoparticles/therapeutic use
- Papillomaviridae/chemistry
- Papillomaviridae/immunology
- Papillomavirus Vaccines/chemistry
- Papillomavirus Vaccines/pharmacology
- Pyrococcus furiosus/chemistry
- Thioredoxins/chemistry
- Thioredoxins/pharmacology
- Uterine Cervical Neoplasms/immunology
- Uterine Cervical Neoplasms/virology
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Affiliation(s)
- Xueer Zhao
- German Cancer Research Center, Heidelberg, Germany
| | - Fan Yang
- German Cancer Research Center, Heidelberg, Germany
| | - Filipe Mariz
- German Cancer Research Center, Heidelberg, Germany
| | - Wolfram Osen
- German Cancer Research Center, Heidelberg, Germany
| | - Angelo Bolchi
- Department of Chemical Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Simone Ottonello
- Department of Chemical Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Martin Müller
- German Cancer Research Center, Heidelberg, Germany
- * E-mail:
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16
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Panahi HA, Bolhassani A, Javadi G, Noormohammadi Z, Agi E. Development of multiepitope therapeutic vaccines against the most prevalent high-risk human papillomaviruses. Immunotherapy 2020; 12:459-479. [DOI: 10.2217/imt-2019-0196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aim: Our goal was the development of DNA- or peptide-based multiepitope vaccines targeting HPV E7, E6 and E5 oncoproteins in tumor mouse model. Materials & methods: After designing the multiepitope E7, E6 and E5 constructs from four types of high risk HPVs (16, 18, 31 & 45) using bioinformatics tools, mice vaccination was performed by different homologous and heterologous modalities in a prophylactic setting. Then, anti-tumor effects of the best prophylactic strategies were studied in a therapeutic setting. Results: In both prophylactic and therapeutic experiments, groups receiving homologous E7+E6+E5 polypeptide, and heterologous E7+E6+E5 DNA prime/polypeptide boost were successful in complete rejection of tumors. Conclusion: The designed multiepitope constructs can be considered as promising candidates to develop effective therapeutic HPV vaccines.
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Affiliation(s)
- Heidar Ali Panahi
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, Iran
- Department of Biology, School of Basic Sciences, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Gholamreza Javadi
- Department of Biology, School of Basic Sciences, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Noormohammadi
- Department of Biology, School of Basic Sciences, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | - Elnaz Agi
- Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
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17
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Mohsen MO, Speiser DE, Knuth A, Bachmann MF. Virus-like particles for vaccination against cancer. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2019; 12:e1579. [PMID: 31456339 PMCID: PMC6916610 DOI: 10.1002/wnan.1579] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/31/2019] [Accepted: 07/16/2019] [Indexed: 12/21/2022]
Abstract
Active immunotherapy of cancer aims to treat the disease by inducing effective cellular and humoral immune responses. Virus‐like particle‐based vaccines have evolved dramatically over the last few decades, greatly reducing morbidity and mortality of several infectious diseases and expectedly preventing cervical cancer caused by human papilloma virus. In contrast to these broad successes of disease prevention, therapeutic cancer vaccines remain to demonstrate clinical benefit. Yet, several preclinical and clinical trials have revealed promising results and are paving the way for medical breakthroughs. This study reviews and discusses the recent preclinical development and clinical trials in this field. This article is categorized under: Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
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Affiliation(s)
- Mona O Mohsen
- The Interim Translational Research Institute "iTRI", National Center for Cancer Care & Research (NCCCR), Doha, Qatar.,Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland
| | - Daniel E Speiser
- Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - Alexander Knuth
- The Interim Translational Research Institute "iTRI", National Center for Cancer Care & Research (NCCCR), Doha, Qatar
| | - Martin F Bachmann
- Department of BioMedical Research, Immunology RIA, University of Bern, Bern, Switzerland.,Nuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford, UK
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18
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Pham CT, Juhasz M, Sung CT, Mesinkovska NA. The human papillomavirus vaccine as a treatment for human papillomavirus-related dysplastic and neoplastic conditions: A literature review. J Am Acad Dermatol 2019; 82:202-212. [PMID: 31085272 DOI: 10.1016/j.jaad.2019.04.067] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/25/2019] [Accepted: 04/26/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
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Affiliation(s)
- Christine T Pham
- University of California, Irvine School of Medicine, Irvine, California; Department of Dermatology, University of California, Irvine, California.
| | - Margit Juhasz
- Department of Dermatology, University of California, Irvine, California
| | - Calvin T Sung
- University of California, Riverside School of Medicine, Riverside, California
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19
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Panahi HA, Bolhassani A, Javadi G, Noormohammadi Z. A comprehensive in silico analysis for identification of therapeutic epitopes in HPV16, 18, 31 and 45 oncoproteins. PLoS One 2018; 13:e0205933. [PMID: 30356257 PMCID: PMC6200245 DOI: 10.1371/journal.pone.0205933] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/11/2018] [Indexed: 11/25/2022] Open
Abstract
Human papillomaviruses (HPVs) are a group of circular double-stranded DNA viruses, showing severe tropism to mucosal tissues. A subset of HPVs, especially HPV16 and 18, are the primary etiological cause for several epithelial cell malignancies, causing about 5.2% of all cancers worldwide. Due to the high prevalence and mortality, HPV-associated cancers have remained as a significant health problem in human society, making an urgent need to develop an effective therapeutic vaccine against them. Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes, inducing a robust cell-mediated immune response. Previous information has shown that E5, E6, and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers. Therefore, the prediction of major histocompatibility complex (MHC) class I T cell epitopes of HPV16, 18, 31 and 45 oncoproteins was targeted in this study. For this purpose, a two-step plan was designed to identify the most probable CD8+ T cell epitopes. In the first step, MHC-I and II binding, MHC-I processing, MHC-I population coverage and MHC-I immunogenicity prediction analyses, and in the second step, MHC-I and II protein-peptide docking, epitope conservation, and cross-reactivity with host antigens’ analyses were carried out successively by different tools. Finally, we introduced five probable CD8+ T cell epitopes for each oncoprotein of the HPV genotypes (60 epitopes in total), which obtained better scores by an integrated approach. These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers. Additionally, this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA- or peptide-based vaccine development.
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Affiliation(s)
- Heidar Ali Panahi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
- * E-mail: ,
| | - Gholamreza Javadi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Noormohammadi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
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20
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Safety and Immunogenicity of a Nonadjuvant Human Papillomavirus Type 6 Virus-like Particle Vaccine in Recurrent Respiratory Papillomatosis. J Voice 2018; 33:363-369. [PMID: 30224308 DOI: 10.1016/j.jvoice.2017.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 11/12/2017] [Accepted: 12/01/2017] [Indexed: 11/23/2022]
Abstract
OBJECTIVES To assess the safety and immunogenicity of a nonadjuvant human papillomavirus (HPV) type 6 L1 virus-like particle (VLP) vaccine in recurrent respiratory papillomatosis (RRP) in local Chinese patients. METHODS Patients with RRP who had undergone surgical treatment before intramuscular administration of an escalating dose of HPV type 6 L1 VLPs (1, 5, and 25 µg at 4 weekly intervals) as part of their treatment were followed up for more than 10 years. Efficacy was assessed by detecting the vaccine-induced type-specific antibody titer, calculating the intersurgical interval, and observing recurrence or remission of papillomas after receiving the vaccine. RESULTS Nonadjuvant HPV vaccine was generally well tolerated, with no serious vaccine-related adverse episodes. It induced seroconversion for each vaccine-related HPV type. At week 12 (4 weeks after injecting 25 µg), the vaccine-induced type-specific antibody titer was significantly high. Analysis of all patients found a significant increase in the intersurgical interval and decrease in the scores. One patient (16.7%; female) experienced complete remission. Five patients (83.3%) (two males and three females) experienced partial remission. In total, complete or partial remission was achieved in six (100%) patients. CONCLUSIONS Administration of nonadjuvant HPV type 6 L1 VLPs vaccine to RRP was generally well tolerated and highly immunogenic.
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21
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Chu X, Li Y, Huang W, Feng X, Sun P, Yao Y, Yang X, Sun W, Bai H, Liu C, Ma Y. Combined immunization against TGF-β1 enhances HPV16 E7-specific vaccine-elicited antitumour immunity in mice with grafted TC-1 tumours. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:1199-1209. [PMID: 29929402 DOI: 10.1080/21691401.2018.1482306] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Therapeutic vaccine appears to be a potential approach for the treatment of human papillomavirus (HPV)-associated tumours, but its efficacy can be dampened by immunosuppressive factors such as transforming growth factor (TGF)-β1. We sought to investigate whether active immunity against TGF-β1 enhances the anti-tumour immunity elicited by an HPV16 E7-specific vaccine that we developed previously. In this study, virus-like particles of hepatitis B virus core antigen were used as vaccine carriers to deliver either TGF-β1 B cell epitopes or E7 cytotoxic T-lymphocyte epitope. The combination of preventive immunization against TGF-β1 and therapeutic immunization with the E7 vaccine significantly reduced the growth of grafted TC-1 tumours in C57 mice, showing better efficacy than immunization with only one of the vaccines. The improved efficacy of combined immunization is evidenced by elevated IFN-γ and decreased IL-4 and TGF-β1 levels in cultured splenocytes, increased E7-specific IFN-γ-expressing splenocytes, and increased numbers of CD4+IFN-γ+ and CD8+IFN-γ+ cells and decreased numbers of Treg (CD4+Foxp3+) cells in the spleen and tumours. The results strongly indicate that targeting TGF-β1 through active immunization might be a potent approach to enhancing antigen-specific therapeutic vaccine-induced anti-tumour immune efficacy and providing a combined strategy for effective cancer immunotherapy.
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Affiliation(s)
- Xiaojie Chu
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yang Li
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Weiwei Huang
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Xuejun Feng
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Pengyan Sun
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yufeng Yao
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Xu Yang
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Wenjia Sun
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Hongmei Bai
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Cunbao Liu
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yanbing Ma
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
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22
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Chabeda A, Yanez RJR, Lamprecht R, Meyers AE, Rybicki EP, Hitzeroth II. Therapeutic vaccines for high-risk HPV-associated diseases. PAPILLOMAVIRUS RESEARCH (AMSTERDAM, NETHERLANDS) 2018; 5:46-58. [PMID: 29277575 PMCID: PMC5887015 DOI: 10.1016/j.pvr.2017.12.006] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/13/2017] [Accepted: 12/17/2017] [Indexed: 12/16/2022]
Abstract
Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described.
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Affiliation(s)
- Aleyo Chabeda
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa
| | - Romana J R Yanez
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa
| | - Renate Lamprecht
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa
| | - Ann E Meyers
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa
| | - Edward P Rybicki
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
| | - Inga I Hitzeroth
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa.
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Abstract
The discovery of genotype 16 as the prototype oncogenic human papillomavirus (HPV) initiated a quarter century of laboratory and epidemiological studies that demonstrated their necessary, but not sufficient, aetiological role in cervical and several other anogenital and oropharyngeal cancers. Early virus-induced immune deviation can lead to persistent subclinical infection that brings the risk of progression to cancer. Effective secondary prevention of cervical cancer through cytological and/or HPV screening depends on regular and widespread use in the general population, but coverage is inadequate in low-resource settings. The discovery that the major capsid antigen L1 could self-assemble into empty virus-like particles (VLPs) that are both highly immunogenic and protective led to the licensure of several prophylactic VLP-based HPV vaccines for the prevention of cervical cancer. The implementation of vaccination programmes in adolescent females is underway in many countries, but their impact critically depends on the population coverage and is improved by herd immunity. This Review considers how our expanding knowledge of the virology and immunology of HPV infection can be exploited to improve vaccine technologies and delivery of such preventive strategies to maximize reductions in HPV-associated disease, including incorporation of an HPV vaccine covering oncogenic types within a standard multitarget paediatric vaccine.
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Affiliation(s)
| | - Peter L. Stern
- Division of Molecular and Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Brun JL, Rajaonarison J, Nocart N, Hoarau L, Brun S, Garrigue I. Targeted immunotherapy of high-grade cervical intra-epithelial neoplasia: Expectations from clinical trials. Mol Clin Oncol 2017; 8:227-235. [PMID: 29435283 DOI: 10.3892/mco.2017.1531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 11/13/2017] [Indexed: 12/20/2022] Open
Abstract
Targeted immunotherapy of high-grade cervical intra-epithelial neoplasia (CIN) has been developed as an alternative to conization, to preserve future reproductive outcomes and avoid human papillomavirus (HPV) persistence. The objectives of the review are to present drugs according to their process of development and to examine their potential future use. A search for key words associated with CIN and targeted immunotherapy was carried out in the Cochrane library, Pubmed, Embase, and ClinicalTrials.gov from 1990 to 2016. Publications (randomized, prospective and retrospective studies) in any language were eligible for inclusion, as well as ongoing trials registered on the ClinicalTrials.gov website. Targeted immunotherapy includes peptide/protein-based vaccines, nucleic acid-based vaccines (DNA), and live vector-based vaccines (bacterial or viral). A total of 18 vaccines were identified for treatment of CIN at various stages of development, and the majority were well-tolerated. Adverse effects were primarily injection site reactions and flu-like symptoms under grade 2. The efficacy of vaccines defined by regression of CIN2/3 to no CIN or CIN1 ranged from 17 to 59% following a minimum of a 12-week follow-up. In the majority of studies, there was no association demonstrated between histological response and HPV clearance, or between histological or virological response and immune T cell response. Given that the spontaneous regression of CIN2/3 is 20-25% at 6 months, targeted immunotherapy occurs an additional value, which never reaches 50%, with one trial an exception to this. However, research and development on HPV eradication drugs needs to be encouraged, due to HPV-associated disease burden.
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Affiliation(s)
- Jean-Luc Brun
- Department of Obstetrics and Gynecology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France.,UMR 5234, Microbiology and Pathogenicity, University of Bordeaux, 33076 Bordeaux, France
| | - José Rajaonarison
- Department of Obstetrics and Gynecology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France
| | - Nicolas Nocart
- Department of Obstetrics and Gynecology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France
| | - Laura Hoarau
- Department of Obstetrics and Gynecology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France
| | - Stéphanie Brun
- Department of Obstetrics and Gynecology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France
| | - Isabelle Garrigue
- UMR 5234, Microbiology and Pathogenicity, University of Bordeaux, 33076 Bordeaux, France.,Laboratory of Virology, Hospital Pellegrin, University of Bordeaux, 33076 Bordeaux, France
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Li J, Chen S, Ge J, Lu F, Ren S, Zhao Z, Pu X, Chen X, Sun J, Gu Y. A novel therapeutic vaccine composed of a rearranged human papillomavirus type 16 E6/E7 fusion protein and Fms-like tyrosine kinase-3 ligand induces CD8 + T cell responses and antitumor effect. Vaccine 2017; 35:6459-6467. [PMID: 29029939 DOI: 10.1016/j.vaccine.2017.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/26/2017] [Accepted: 09/03/2017] [Indexed: 01/15/2023]
Abstract
The development of cervical cancer is mainly caused by infection with high risk genotypes of human papillomavirus, particularly type 16 (HPV16), which accounts for more than 50% of cervical cancer. The two early viral oncogenes, E6 and E7, are continuously expressed in cervical cancer cells and are necessary to maintain the malignant cellular phenotype, thus providing ideal targets for immunotherapy of cervical cancer. In this study, a novel vaccine strategy was developed based on a rationally shuffled HPV16 E6/E7 fusion protein, the addition of Fms-like tyrosine kinase-3 ligand (Flt3L) or the N domain of calreticulin (NCRT), and the usage of a CpG adjuvant. Four recombinant proteins were constructed: m16E6E7 (mutant E6/E7 fusion protein), rm16E6E7 (rearranged mutant HPV16 E6/E7 fusion protein), Flt3L-RM16 (Flt3L fused to rm16E6E7), and NCRT-RM16 (NCRT fused to rm16E6E7). Our results suggest that Flt3L-RM16 was the most potent of these proteins in terms of inducing E6- and E7-specific CD8+ T cell responses. Additionally, Flt3L-RM16 significantly induced regression of established E6/E7-expressing TC-1 tumors. Higher doses of Flt3L-RM16 trended toward higher levels of antitumor activity, but these differences did not reach statistical significance. In summary, this study found that Flt3L-RM16 fusion protein is a promising therapeutic vaccine for immunotherapy of HPV16-associated cervical cancer.
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Affiliation(s)
- Jianqiang Li
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Si Chen
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Jun Ge
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Feng Lu
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Sulin Ren
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Zhiqiang Zhao
- Suzhou Yuankang Bio-pharmaceutical Co., Ltd., Suzhou, China.
| | - Xiuying Pu
- Suzhou Yuankang Bio-pharmaceutical Co., Ltd., Suzhou, China.
| | - Xiaoxiao Chen
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Jiaojiao Sun
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Yueqing Gu
- China Pharmaceutical University, Nanjing, China.
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Rosales C, Rosales R. Prophylactic and Therapeutic Vaccines against Human Papillomavirus Infections. Vaccines (Basel) 2017. [DOI: 10.5772/intechopen.69548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Pouyanfard S, Müller M. Human papillomavirus first and second generation vaccines-current status and future directions. Biol Chem 2017; 398:871-889. [PMID: 28328521 DOI: 10.1515/hsz-2017-0105] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 03/16/2017] [Indexed: 02/06/2023]
Abstract
It has been more than 10 years that the first prophylactic papillomavirus vaccine became available, although distribution has been mainly limited to the more affluent countries. The first two vaccines have been a great success, hundreds of millions of women and a much smaller number of men have been vaccinated ever since. In a few countries with high vaccination coverage, in particular Australia but also parts of Great Britain and others, clinical impact of vaccination programs is already visible and there are indications for herd immunity as well. Vaccine efficacy is higher than originally estimated and the vaccines have an excellent safety profile. Gardasil9 is a second generation HPV virus-like particle vaccine that was licensed in 2015 and there are more to come in the near future. Currently, burning questions in respect to HPV vaccination are the duration of protection - especially in regard to cross-protection - reduction of the three-dose regimen and its impact on cross-protection; and duration of response, as well as protection against oropharyngeal HPV infections. Furthermore, researchers are seeking to overcome limitations of the VLP vaccines, namely low thermal stability, cost, invasive administration, limited coverage of non-vaccine HPV types, and lack of therapeutic efficacy. In this review we summarize the current status of licensed VLP vaccines and address questions related to second and third generation HPV vaccines.
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Diorio GJ, Giuliano AR. The Role of Human Papilloma Virus in Penile Carcinogenesis and Preneoplastic Lesions. Urol Clin North Am 2016; 43:419-425. [DOI: 10.1016/j.ucl.2016.06.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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CD8 + T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer. Eur J Cancer 2016; 67:141-151. [PMID: 27669501 DOI: 10.1016/j.ejca.2016.08.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 08/16/2016] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Immunological response to human papillomavirus (HPV) in the development and progression of HPV16+ oropharyngeal squamous cell carcinoma (OPSCC) (accounting for the majority of viral associated cases) is largely unknown and may provide important insights for new therapeutic strategies. METHODS In this prospective clinical trial (UKCRN11945), we examined cell-mediated immune responses to HPV16 E2, E6 and E7 in peripheral blood using IFN-γ enzyme-linked immunosorbent spot assay. CD56+, CD4+, CD8+ and regulatory T cell frequencies were also discerned by flow cytometry. Fifty-one study participants with oropharyngeal carcinoma were recruited. Control subjects were those undergoing tonsillectomy for benign disease. All patients were treated with curative intent by radiotherapy ± chemotherapy. Disease-specific survival was investigated by multivariate analysis. RESULTS HPV16 DNA was detected in 41/51 of the OPSCC participants. T cell responses against HPV16 E6 or E7 peptides were detected in 33/51 evaluable patients, respectively and correlated with HPV status. Matched pre- and post-treatment T cell responses were available for 39/51 OPSCC cases. Within the whole cohort, elevated post-treatment CD8+ response to HPV16 E7 correlated with longer disease free survival (multivariate DFS p < 0.03). Within the HPV + OPSCC cohort, a significant increase in regulatory T cells (p < 0.02) was noted after treatment. CONCLUSIONS This is the first study to provide survival data in OPSCC stratified by cell-mediated immune response to HPV16 peptides. Within the HPV16+ OPSCC cohort, enhanced immunoreactivity to antigen E7 was linked to improved survival. An increase in regulatory T cell frequencies after treatment may suggest that immunosuppression can contribute to a reduced HPV-specific cell-mediated response.
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Sabah SN, Gazi MA, Sthity RA, Husain AB, Quyyum SA, Rahman M, Islam MR. Designing of Epitope-Focused Vaccine by Targeting E6 and E7 Conserved Protein Sequences: An Immuno-Informatics Approach in Human Papillomavirus 58 Isolates. Interdiscip Sci 2016; 10:251-260. [PMID: 27640170 DOI: 10.1007/s12539-016-0184-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 08/02/2016] [Accepted: 09/02/2016] [Indexed: 10/21/2022]
Abstract
Human papillomavirus (HPV) is a DNA virus that belongs to the papillomavirus family and is capable of infecting humans. Currently, few vaccines are available to prevent infection by HPV. However, they are not so much effective and provide little benefit to women who have already been infected with HPV. The aim of this study was to design epitope-based vaccines of HPV58 by targeting E6 and E7 proteins of HPV58. Proteomic sequences were retrieved from different isolates at different time periods and later analyzed by performing alignment of these sequences. To ensure the capacity of humoral and cell-mediated immunity, both B cell and T cell immunity were checked for the peptides. For E6 protein, the peptide sequence from 48 to 54 amino acids and one 9-m epitope ETSVHEIEL were the most potential B cell and T cell epitopes, respectively. This peptide could interact with as many as eight MHC-1 alleles and showed high population coverage up to 90.31 %. On the other hand, the peptide region for the E7 protein ranged from 27 to 33 amino acids and two 9-m epitopes QAQPATANY, SSDEDEIGL were found as the most potential B cell and T cell epitopes, respectively. The peptide sequences could interact with as many as seven MHC-1 alleles and showed population coverage up to 90.31 %. Furthermore, conservancy analysis was also performed using in silico tools and showed a conservancy of 100 % for all the selected epitopes. In addition to this, the allergenicity of the epitopes was also evaluated. Although the study requires further in vitro and in vivo screening, this epitope-focused peptide vaccine designing opens up a new skyline that holds a prospective future in HPV research.
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Affiliation(s)
| | - Md Amran Gazi
- Nutrition and Clinical Services Division, Centre for Nutrition and Food Security, International Centre for Diarrhoeal Disease Research, GPO Box 128, Dhaka, 1000, Bangladesh.
| | - Rahvia Alam Sthity
- Immunobiology, Nutrition and Toxicology Laboratory, International Centre for Diarrheal Disease Research, Dhaka, Bangladesh
| | - Amena Binte Husain
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Salwa Abdul Quyyum
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Mustafizur Rahman
- Center for Bio-Medical Research, Manarat University, Dhaka, Bangladesh
| | - Md Rezaul Islam
- International Max Planck Research School, University of Göttingen, 37075, Göttingen, Germany.
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Lee KL, Twyman RM, Fiering S, Steinmetz N. Virus-based nanoparticles as platform technologies for modern vaccines. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2016; 8:554-78. [PMID: 26782096 PMCID: PMC5638654 DOI: 10.1002/wnan.1383] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/11/2015] [Indexed: 12/25/2022]
Abstract
Nanoscale engineering is revolutionizing the development of vaccines and immunotherapies. Viruses have played a key role in this field because they can function as prefabricated nanoscaffolds with unique properties that are easy to modify. Viruses are immunogenic via multiple pathways, and antigens displayed naturally or by engineering on the surface can be used to create vaccines against the cognate virus, other pathogens, specific molecules or cellular targets such as tumors. This review focuses on the development of virus-based nanoparticle systems as vaccines indicated for the prevention or treatment of infectious diseases, chronic diseases, cancer, and addiction. WIREs Nanomed Nanobiotechnol 2016, 8:554-578. doi: 10.1002/wnan.1383 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Karin L. Lee
- Department of Biomedical Engineering, Case Western Reserve University Schools of Engineering and Medicine, Cleveland, OH 44106
| | | | - Steven Fiering
- Department of Microbiology and Immunology and Norris Cotton Cancer Center, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756
| | - Nicole Steinmetz
- Departments of Biomedical Engineering, Radiology, Materials Science and Engineering, and Macromolecular Science and Engineering, Case Western Reserve University and Medicine, Cleveland, OH 44106;
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Van Damme P, Bouillette-Marussig M, Hens A, De Coster I, Depuydt C, Goubier A, Van Tendeloo V, Cools N, Goossens H, Hercend T, Timmerman B, Bissery MC. GTL001, A Therapeutic Vaccine for Women Infected with Human Papillomavirus 16 or 18 and Normal Cervical Cytology: Results of a Phase I Clinical Trial. Clin Cancer Res 2016; 22:3238-48. [PMID: 27252412 DOI: 10.1158/1078-0432.ccr-16-0085] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/13/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE Women infected with human papillomavirus (HPV) with normal cytology to mild abnormalities currently have no treatment options other than watchful waiting or surgery if high-grade cervical lesions or cancer develop. A therapeutic vaccine would offer the possibility of preventing high-grade lesions in HPV-infected women. GTL001 is a therapeutic vaccine composed of recombinant HPV16 and HPV18 E7 proteins fused to catalytically inactive Bordetella pertussis CyaA. This study examined the tolerability and immunogenicity of GTL001 in women infected with HPV16 or HPV18 with normal cytology. EXPERIMENTAL DESIGN This was a phase I trial (EudraCT No. 2010-018629-21). In an open-label part, subjects received two intradermal vaccinations 6 weeks apart of 100 or 600 μg GTL001 + topical 5% imiquimod cream at the injection site. In a double-blind part, subjects were randomized 2:1:1 to two vaccinations 6 weeks apart of 600 μg GTL001 + imiquimod, 600 μg GTL001 + placebo cream, or placebo + imiquimod. RESULTS Forty-seven women were included. No dropouts, treatment-related serious adverse events, or dose-limiting toxicities occurred. Local reactions were transient and mostly mild or moderate. HPV16/18 viral load decreased the most in the 600 μg GTL001 + imiquimod group. In post hoc analyses, the 600 μg GTL001 + imiquimod group had the highest rates of initial and sustained HPV16/18 clearance. Imiquimod increased antigen-specific T-cell response rates but not rates of solicited reactions. All subjects seroconverted to CyaA. CONCLUSIONS For women infected with HPV16 or HPV18 with normal cervical cytology, GTL001 was immunogenic and had acceptable safety profile. Clin Cancer Res; 22(13); 3238-48. ©2016 AACR.
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Affiliation(s)
| | | | | | | | - Christophe Depuydt
- Department of Molecular Diagnostics, AML, Sonic Healthcare, Antwerp, Belgium
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Michon C, Langella P, Eijsink VGH, Mathiesen G, Chatel JM. Display of recombinant proteins at the surface of lactic acid bacteria: strategies and applications. Microb Cell Fact 2016; 15:70. [PMID: 27142045 PMCID: PMC4855500 DOI: 10.1186/s12934-016-0468-9] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 04/21/2016] [Indexed: 01/07/2023] Open
Abstract
Lactic acid bacteria (LAB) are promising vectors of choice to deliver active molecules to mucosal tissues. They are recognized as safe by the World Health Organization and some strains have probiotic properties. The wide range of potential applications of LAB-driven mucosal delivery includes control of inflammatory bowel disease, vaccine delivery, and management of auto-immune diseases. Because of this potential, strategies for the display of proteins at the surface of LAB are gaining interest. To display a protein at the surface of LAB, a signal peptide and an anchor domain are necessary. The recombinant protein can be attached to the membrane layer, using a transmembrane anchor or a lipoprotein-anchor, or to the cell wall, by a covalent link using sortase mediated anchoring via the LPXTG motif, or by non-covalent liaisons employing binding domains such as LysM or WxL. Both the stability and functionality of the displayed proteins will be affected by the kind of anchor used. The most commonly surfaced exposed recombinant proteins produced in LAB are antigens and antibodies and the most commonly used LAB are lactococci and lactobacilli. Although it is not necessarily so that surface-display is the preferred localization in all cases, it has been shown that for certain applications, such as delivery of the human papillomavirus E7 antigen, surface-display elicits better biological responses, compared to cytosolic expression or secretion. Recent developments include the display of peptides and proteins targeting host cell receptors, for the purpose of enhancing the interactions between LAB and host. Surface-display technologies have other potential applications, such as degradation of biomass, which is of importance for some potential industrial applications of LAB.
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Affiliation(s)
- C. Michon
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - P. Langella
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
| | - V. G. H. Eijsink
- />Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - G. Mathiesen
- />Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - J. M. Chatel
- />Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France
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López-Toledo G, Schädlich L, Alonso-Castro ÁJ, Monroy-García A, García-Rocha R, Guido MC, Gissmann L, García-Carrancá A. Immunization with Human Papillomavirus 16 L1+E2 Chimeric Capsomers Elicits Cellular Immune Response and Antitumor Activity in a Mouse Model. Viral Immunol 2016; 29:276-87. [PMID: 27058179 DOI: 10.1089/vim.2015.0080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Development of cervical cancer is associated with persistent infections by high-risk human papillomavirus (HPV). Although current HPV L1-based prophylactic vaccines prevent infection, they do not help to eliminate prevalent infections or lesions. Our aims were (i) to generate a vaccine combining prophylactic and therapeutic properties by producing chimeric capsomers after fusion of the L1 protein to different fragments of E2 from HPV 16, and (ii) to evaluate their capacity to generate an antitumoral cellular response, while conserving L1 neutralizing epitopes. Chimeric proteins were produced in Escherichia coli and purified by glutathione S-transferase (GST)-affinity chromatography. Their structure was characterized using size exclusion chromatography, sucrose gradient centrifugation, electron microscopy, and anti-L1 enzyme-linked immunosorbent assay. All chimeric proteins form capsomers and heterogeneous aggregates. One, containing part of the carboxy-terminal domain of E2 and its hinge region (L1Δ+E2H/NC, aa 206-307), conserved the neutralizing epitope H16.V5. We then evaluated the capacity of this chimeric protein to induce a cytotoxic T-cell response against HPV 16 E2. In (51)Cr release cytotoxicity assays, splenocytes from C57BL/6 immunized mice recognized and lysed TC-1/E2 cells, which express and present endogenously processed E2 peptides. Moreover, this E2-specific cytotoxic response inhibited the growth of tumors of TC-1/E2 cells in mice. Finally, we identified an epitope (aa 292-301) of E2 involved in this cytotoxic response. We conclude that the L1Δ+E2H/NC chimeric protein produced in bacteria can be an effective and economically interesting candidate for a combined prophylactic and therapeutic vaccine that could help eliminating HPV16-positive low-grade cervical lesions and persistent viral infections, thus preventing the development of lesions and, at the same time, the establishment of new infections.
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Affiliation(s)
- Gabriela López-Toledo
- 1 Department of Molecular Biology and Biotechnology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Mexico City, Mexico .,2 Laboratory of Virus and Cancer, Division of Basic Research, Instituto Nacional de Cancerología-SS , Mexico City, Mexico
| | - Lysann Schädlich
- 3 Division of Genome Modifications and Carcinogenesis, German Cancer Research Center (DKFZ) , Heidelberg, Germany
| | - Ángel Josabad Alonso-Castro
- 2 Laboratory of Virus and Cancer, Division of Basic Research, Instituto Nacional de Cancerología-SS , Mexico City, Mexico
| | - Alberto Monroy-García
- 4 Laboratory of Immunobiology, Facultad de Estudios Superiores Zaragoza , Unidad de Investigación en Diferenciación Celular y Cáncer, UMIEZ, UNAM, Mexico City, Mexico .,5 Laboratory of Immunology and Cancer, Unidad de Investigación Médica en Enfermedades Oncológicas , CMN SXXI, IMSS, Mexico City, Mexico
| | - Rosario García-Rocha
- 5 Laboratory of Immunology and Cancer, Unidad de Investigación Médica en Enfermedades Oncológicas , CMN SXXI, IMSS, Mexico City, Mexico .,6 Department of Immunology, Escuela Nacional de Ciencias Biológicas , IPN, Mexico City, Mexico
| | - Miriam C Guido
- 1 Department of Molecular Biology and Biotechnology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Mexico City, Mexico .,2 Laboratory of Virus and Cancer, Division of Basic Research, Instituto Nacional de Cancerología-SS , Mexico City, Mexico
| | - Lutz Gissmann
- 3 Division of Genome Modifications and Carcinogenesis, German Cancer Research Center (DKFZ) , Heidelberg, Germany
| | - Alejandro García-Carrancá
- 1 Department of Molecular Biology and Biotechnology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Mexico City, Mexico .,2 Laboratory of Virus and Cancer, Division of Basic Research, Instituto Nacional de Cancerología-SS , Mexico City, Mexico
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Koeneman MM, Kruse AJ, Kooreman LFS, Zur Hausen A, Hopman AHN, Sep SJS, Van Gorp T, Slangen BFM, van Beekhuizen HJ, van de Sande M, Gerestein CG, Nijman HW, Kruitwagen RFPM. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer 2016; 16:132. [PMID: 26897518 PMCID: PMC4761416 DOI: 10.1186/s12885-016-2187-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 02/16/2016] [Indexed: 11/10/2022] Open
Abstract
Background Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5 % cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities. Methods/design The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2–3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment. Discussion Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary. Trial registration EU Clinical Trials Register EU-CTR2013-001260-34. Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171.
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Affiliation(s)
- M M Koeneman
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands. .,GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
| | - A J Kruse
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - L F S Kooreman
- Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - A Zur Hausen
- Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - A H N Hopman
- GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.,Department of Molecular Cell Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - S J S Sep
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - T Van Gorp
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - B F M Slangen
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - H J van Beekhuizen
- Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - M van de Sande
- Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - C G Gerestein
- Department of Obstetrics and Gynaecology, Meander Medical Center, Amersfoort, The Netherlands
| | - H W Nijman
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, Groningen, The Netherlands
| | - R F P M Kruitwagen
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
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Menderes G, Black J, Schwab CL, Santin AD. Immunotherapy and targeted therapy for cervical cancer: an update. Expert Rev Anticancer Ther 2015; 16:83-98. [PMID: 26568261 DOI: 10.1586/14737140.2016.1121108] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8-13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. In the last few years, a better understanding of Human papillomavirus tumor-host immune system interactions and the development of new therapeutics targeting immune check points have renewed interest in the use of immunotherapy in cervical cancer patients. Moreover, next generation sequencing has emerged as an attractive option for the identification of actionable driver mutations and other markers. In this review, we provide background information on the molecular biology of cervical cancer and summarize immunotherapy studies, targeted therapies, including those with angiogenesis inhibitors and tyrosine kinase inhibitors recently completed or currently on-going in cervical cancer patients.
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Affiliation(s)
- Gulden Menderes
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Jonathan Black
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Carlton L Schwab
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
| | - Alessandro D Santin
- a Department of Obstetrics, Gynecology & Reproductive Sciences , Yale University School of Medicine , New Haven , CT , USA
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McKee SJ, Bergot AS, Leggatt GR. Recent progress in vaccination against human papillomavirus-mediated cervical cancer. Rev Med Virol 2015; 25 Suppl 1:54-71. [PMID: 25752816 DOI: 10.1002/rmv.1824] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
It has been more than 7 years since the commercial introduction of highly successful vaccines protecting against high-risk human papillomavirus (HPV) subtypes and the development of cervical cancer. From an immune standpoint, the dependence of cervical cancer on viral infection has meant that HPV proteins can be targeted as strong tumour antigens leading to clearance of the infection and the subsequent protection from cancer. Commercially available vaccines consisting of the L1 capsid protein assembled as virus-like particles (VLPs) induce neutralising antibodies that deny access of the virus to cervical epithelial cells. While greater than 90% efficacy has been demonstrated at the completion of large phase III trials in young women, vaccine developers are now addressing broader issues such as efficacy in boys, longevity of the protection and inducing cross-reactive antibody for oncogenic, non-vaccine HPV strains. For women with existing HPV infection, the prophylactic vaccines provide little protection, and consequently, the need for therapeutic vaccines will continue into the future. Therapeutic vaccines targeting HPVE6 and E7 proteins are actively being pursued with new adjuvants and delivery vectors, combined with an improved knowledge of the tumour microenvironment, showing great promise. This review will focus on recent progress in prophylactic and therapeutic vaccine development and implementation since the publication of end of study data from phase III clinical trials between 2010 and 2012.
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Affiliation(s)
- Sara J McKee
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
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Abstract
The two licensed bivalent and quadrivalent human papillomavirus (HPV) L1 (the major papillomavirus virion protein) virus-like particle (VLP) vaccines are regarded as safe, effective, and well established prophylactic vaccines. However, they have some inherent limitations, including a fairly high production and delivery cost, virus-type restricted protection, and no reported therapeutic activity, which might be addressed with the development of alternative dosing schedules and vaccine products. A change from a three-dose to a two-dose protocol for the licensed HPV vaccines, especially in younger adolescents (aged 9-13 years), is underway in several countries and is likely to become the future norm. Preliminary evidence suggests that recipients of HPV vaccines might derive prophylactic benefits from one dose of the bivalent vaccine. Substantial interest exists in both the academic and industrial sectors in the development of second-generation L1 VLP vaccines in terms of cost reduction-eg, by production in Escherichia coli or alternative types of yeast. However, Merck's nonavalent vaccine, produced via the Saccharomyces cerevisiae production system that is also used for their quadrivalent vaccine, is the first second-generation HPV VLP vaccine to be available on the market. By contrast, other pharmaceutical companies are developing microbial vectors that deliver L1 genes. These two approaches would add an HPV component to existing live attenuated vaccines for measles and typhoid fever. Prophylactic vaccines that are based on induction of broadly cross-neutralising antibodies to L2, the minor HPV capsid protein, are also being developed both as simple monomeric fusion proteins and as virus-like display vaccines. The strong interest in developing the next generation of vaccines, particularly by manufacturers in middle-to-high income countries, increases the likelihood that vaccine production will become decentralised with the hope that effective HPV vaccines will be made increasingly available in low-resource settings where they are most needed.
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Gonçalves AK, Giraldo PC, Machado PRL, Farias KJS, Costa APF, Freitas JCDOC, Eleutério J, Witkin SS. Human Papillomavirus Vaccine-Induced Cytokine Messenger RNA Expression in Vaccinated Women. Viral Immunol 2015; 28:339-42. [DOI: 10.1089/vim.2015.0008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Ana Katherine Gonçalves
- Department of Gynecology and Obstetrics, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Paulo César Giraldo
- Department of Gynecology and Obstetrics, State University of Campinas, Campinas, Brazil
| | - Paula Renata Lima Machado
- Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | - Ana Paula Ferreira Costa
- Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, Brazil
| | | | - José Eleutério
- Department of Gynecology and Obstetrics, Federal University of Ceará, Fortaleza, Brazil
| | - Steven S. Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York
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Ghosn M, Kourie HR, Abdayem P, Antoun J, Nasr D. Anal cancer treatment: Current status and future perspectives. World J Gastroenterol 2015; 21:2294-2302. [PMID: 25741135 PMCID: PMC4342904 DOI: 10.3748/wjg.v21.i8.2294] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Revised: 10/24/2014] [Accepted: 12/22/2014] [Indexed: 02/07/2023] Open
Abstract
Anal cancers (AC) are relatively rare tumors. Their incidence is increasing, particularly among men who have sex with other men due to widespread infection by human papilloma virus. The majority of anal cancers are squamous cell carcinomas, and they are treated according to stage. In local and locally advanced AC, concomitant chemoradiation therapy based on mitomycin C and 5-Fluorouracil (5-FU) is the current best treatment, while metastatic AC, chemotherapy with 5-FU and cisplatin remains the gold standard. There are no indications for induction or maintenance therapies in locally advanced tumors. Many novel strategies, such as targeted therapies, vaccination, immunotherapy and photodynamic therapy are in clinical trials for the treatment of AC, with promising results in some indications.
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Human Papillomavirus Vaccine. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 101:231-322. [DOI: 10.1016/bs.apcsb.2015.08.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Oral vaccination against HPV E7 for treatment of cervical intraepithelial neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in the cervix of CIN3 patients. Vaccine 2014; 32:6233-9. [PMID: 25258102 DOI: 10.1016/j.vaccine.2014.09.020] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 07/28/2014] [Accepted: 09/08/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cervical intraepithelial neoplasia grade 3 (CIN3) is a mucosal precancerous lesion caused by high-risk human papillomavirus (HPV). Induction of immunological clearance of CIN3 by targeting HPV antigens is a promising strategy for CIN3 therapy. No successful HPV therapeutic vaccine has been developed. METHODS We evaluated the safety and clinical efficacy of an attenuated Lactobacillus casei expressing modified full-length HPV16 E7 protein in patients with HPV16-associated CIN3. Ten patients were vaccinated orally during dose optimization studies (1, 2, 4, or 6 capsules/day) at weeks 1, 2, 4, and 8 (Step 1). Seven additional participants were only tested using the optimized vaccine formulation (Step 2), giving a total of 10 patients who received optimized vaccination. Cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were collected and E7 specific interferon-γ-producing cells were counted (E7 cell-mediated immune responses: E7-CMI) by ELISPOT assay. All patients were re-evaluated 9 weeks after initial vaccine exposure using cytology and biopsy to assess pathological efficacy. RESULTS No patient experienced an adverse event. E7-CMI in both CxLs and PBMCs was negligible at baseline. All patients using 4-6 capsules/day showed increased E7-CMI in CxLs, whereas patients using 1-2 capsules/day did not. No patient demonstrated an increase in E7-CMI in their PBMCs. In comparison between patients of cohorts, E7-CMI at week 9 (9 wk) in patients on 4 capsules/day was significantly higher than those in patients on 1, 2, or 6 capsules/day. Most patients (70%) taking the optimized dose experienced a pathological down-grade to CIN2 at week 9 of treatment. E7-CMI in CxLs correlated directly with the pathological down-grade. CONCLUSIONS Oral administration of an E7-expressing Lactobacillus-based vaccine can elicit E7-specific mucosal immunity in the uterine cervical lesions. We are the first to report a correlation between mucosal E7-CMI in the cervix and clinical response after immunotherapy in human mucosal neoplasia.
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Meyer SI, Fuglsang K, Blaakaer J. Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination. Acta Obstet Gynecol Scand 2014; 93:1209-18. [DOI: 10.1111/aogs.12480] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 08/12/2014] [Indexed: 11/29/2022]
Affiliation(s)
- Sonja Izquierdo Meyer
- Department of Obstetrics and Gynecology; Aarhus University Hospital, Skejby; Aarhus Denmark
| | - Katrine Fuglsang
- Department of Obstetrics and Gynecology; Aarhus University Hospital, Skejby; Aarhus Denmark
| | - Jan Blaakaer
- Department of Obstetrics and Gynecology; Aarhus University Hospital, Skejby; Aarhus Denmark
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Chen S, Wang X, Wu X, Wei MQ, Zhang B, Liu X, Wang Y. IL-10 signalling blockade at the time of immunization inhibits Human papillomavirus 16 E7 transformed TC-1 tumour cells growth in mice. Cell Immunol 2014; 290:145-51. [DOI: 10.1016/j.cellimm.2014.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 05/15/2014] [Accepted: 06/10/2014] [Indexed: 12/30/2022]
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Wang SX, Zhang XS, Guan HS, Wang W. Potential anti-HPV and related cancer agents from marine resources: an overview. Mar Drugs 2014; 12:2019-35. [PMID: 24705500 PMCID: PMC4012449 DOI: 10.3390/md12042019] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 03/10/2014] [Accepted: 03/14/2014] [Indexed: 12/14/2022] Open
Abstract
Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown to possess a variety of anti-HPV and related cancer activities. This paper will review the recent progress in research on the potential anti-HPV and related cancer agents from marine resources. In particular, it will provide an update on the anti-HPV actions of heparinoid polysaccharides and bioactive compounds present in marine organisms, as well as the therapeutic vaccines relating to marine organisms. In addition, the possible mechanisms of anti-HPV actions of marine bioactive compounds and their potential for therapeutic application will also be summarized in detail.
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Affiliation(s)
- Shi-Xin Wang
- Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China.
| | - Xiao-Shuang Zhang
- Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China.
| | - Hua-Shi Guan
- Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China.
| | - Wei Wang
- Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao 266003, China.
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Vici P, Mariani L, Pizzuti L, Sergi D, Di Lauro L, Vizza E, Tomao F, Tomao S, Cavallotti C, Paolini F, Venuti A. Immunologic treatments for precancerous lesions and uterine cervical cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:29. [PMID: 24667138 PMCID: PMC3986944 DOI: 10.1186/1756-9966-33-29] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 03/18/2014] [Indexed: 01/24/2023]
Abstract
Development of HPV-associated cancers not only depends on efficient negative regulation of cell cycle control that supports the accumulation of genetic damage, but also relies on immune evasion that enable the virus to go undetected for long periods of time. In this way, HPV-related tumors usually present MHC class I down-regulation, impaired antigen-processing ability, avoidance of T-cell mediated killing, increased immunosuppression due to Treg infiltration and secrete immunosuppressive cytokines. Thus, these are the main obstacles that immunotherapy has to face in the treatment of HPV-related pathologies where a number of different strategies have been developed to overcome them including new adjuvants. Although antigen-specific immunotherapy induced by therapeutic HPV vaccines was proved extremely efficacious in pre-clinical models, its progression through clinical trials suffered poor responses in the initial trials. Later attempts seem to have been more promising, particularly against the well-defined precursors of cervical, anal or vulvar cancer, where the local immunosuppressive milieu is less active. This review focuses on the advances made in these fields, highlighting several new technologies (such as mRNA vaccine, plant-derived vaccine). The most promising immunotherapies used in clinical trials are also summarized, along with integrated strategies, particularly promising in controlling tumor metastasis and in eliminating cancer cells altogether. After the early promising clinical results, the development of therapeutic HPV vaccines need to be implemented and applied to the users in order to eradicate HPV-associated malignancies, eradicating existing perception (after the effectiveness of commercial preventive vaccines) that we have already solved the problem.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Aldo Venuti
- HPV Unit, Regina Elena National Cancer Institute, V Elio Chianesi 53, Rome 00144, Italy.
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Marcuzzi GP, Awerkiew S, Hufbauer M, Schädlich L, Gissmann L, Eming S, Pfister H. Tumor prevention in HPV8 transgenic mice by HPV8-E6 DNA vaccination. Med Microbiol Immunol 2014; 203:155-63. [PMID: 24446083 DOI: 10.1007/s00430-014-0327-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 01/09/2014] [Indexed: 12/11/2022]
Abstract
The genus beta human papillomavirus 8 (HPV8) is involved in the development of cutaneous squamous cell carcinomas (SCCs) in individuals with epidermodysplasia verruciformis. Immunosuppressed transplant recipients are prone to harbor particularly high betapapillomavirus DNA loads, which may contribute to their highly increased risk of SCC. Tumor induction in HPV8 transgenic mice correlates with increased expression of viral oncogenes E6 and E2. In an attempt to prevent skin tumor development, we evaluated an HPV8-E6-DNA vaccine, which was able to stimulate a detectable HPV8-E6-specific cell-mediated immune response in 8/15 immunized mice. When skin of HPV8 transgenic mice was grafted onto non-transgenic littermates, the grafted HPV8 transgenic tissue was not rejected and papillomas started to grow within 14 days all over the transplant of 9/9 non-vaccinated and 7/15 not successfully vaccinated mice. In contrast, no papillomas developed in 6/8 successfully vaccinated mice. In the other two of these eight mice, a large ulcerative lesion developed within the initial papilloma growth or papilloma development was highly delayed. As the vaccine completely or partially prevented papilloma development without rejecting the transplanted HPV8 positive skin, the immune system appears to attack only keratinocytes with increased levels of E6 protein, which would give rise to papillomas.
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Affiliation(s)
- Gian Paolo Marcuzzi
- Institute of Virology, University of Cologne, Fuerst-Pueckler-Str. 56, 50935, Cologne, Germany
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Sin JI. Promises and challenges of human papillomavirus vaccines for cervical cancer. Expert Rev Anticancer Ther 2014; 9:1-5. [DOI: 10.1586/14737140.9.1.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Giorgi C, Franconi R, Rybicki EP. Human papillomavirus vaccines in plants. Expert Rev Vaccines 2014; 9:913-24. [DOI: 10.1586/erv.10.84] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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[Development of new therapies targeting human papillomavirus molecules]. Uirusu 2014; 64:35-42. [PMID: 25765978 DOI: 10.2222/jsv.64.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
High-risk HPV E6 and E7 oncogenes are an ideal targeting gene for treatment of cervical cancer. In this paper, we introduce researches on cancer-immunotherapy targeting HPV E7 through mucosal immunity and E6/E7-targeting siRNA therapy using PEGylated polymeric micelles. Therapeutic HPV vaccine has also attracted attention as a cancer immunotherapy agent. We have found homing of Integrin β7-positive intestinal mucosal lymphocyte on the cervical mucosa. In this study, we generated a novel therapeutic vaccine; an HPV E7-expressing Lactobacillus casei (LacE7) to induce anti-HPV cellular immunity directly to intestinal mucosa. Cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were counted E7 specific INFγ-producing cells (E7 cell-mediated immune responses: E7-CMI) by ELISPOT assay. We confirmed induction of anti-E7 IFNγ-producing cells in the cervix lymphocytes obtained from these patients. E6/E7 siRNA therapy requires a delivery system for its systemic intravenous administration. We here demonstrated that intravenous injection of HPV16 or 18 E6/E7 siRNA polymeric micelles suppressed excellently an increase in size of subcutaneous tumor formed by SiHa or HeLa cell, respectively. Our drug-delivery technology using polymeric micelles enabled the successful systemic administration of siRNA to exhibit anti-tumor effect.
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