Reviews in Medical Virology

REVIEW

Rev. Med. Virol. 2015; 25: 54–71. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1824

Recent progress in vaccination against human papillomavirus-mediated cervical cancer Sara J. McKee†, Anne-Sophie Bergot† and Graham R. Leggatt* The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia

S U M M A RY It has been more than 7 years since the commercial introduction of highly successful vaccines protecting against highrisk 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. Copyright © 2015 John Wiley & Sons, Ltd.

INTRODUCTION Targeting cancers for immunotherapy is often complicated by a lack of immunogenic tumour peptides. Mutated or overexpressed self-antigens are frequently the targets and invoke a generally low affinity/avidity T and B cell response. In contrast, the tight association between infection with HPV and cervical cancer means that foreign viral proteins encoded by HPV can provide the basis of either prophylactic or therapeutic cancer vaccines [1,2]. The natural course of anogenital HPV infection results in overwhelming clearance of the virus in 98% of individuals with an immune component

*Correspondence to: G. Leggatt, University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, Australia, 4102. E-mail: [email protected] † These authors contributed equally. Abbreviations DC, dendritic cell; HPV, human papillomavirus; TLR, toll-like receptor; VIN, vulvar epithelial neoplasia; VLP, virus-like particle.

Copyright © 2015 John Wiley & Sons, Ltd.

suggested by the increased risk of HPV-associated cancers in immune-compromised organ transplant recipients [3,4]. However, HPV genotype-specific antibodies against the viral capsid proteins (L1 and L2) are produced at only low levels in about half the patients, can take close to a year to develop after natural infection and associate with higher viral loads in the cervix [5]. Thus, natural antibody may reflect the non-lytic, localised, intracellular nature of the infection leading to poor immunogenicity for immunoglobulin production and a greater emphasis on T-cell immunity for viral clearance. In contrast, prior immunization with HPV capsid proteins in animal studies induces high titres of antibody that are protective against challenge infection. Early studies in dogs demonstrated that prior immunization with L1 capsid protein could protect beagles from mucosal challenge with canine oral papillomavirus and that serum immunoglobulins could transfer this protection [6]. Given the inability to efficiently grow papillomaviruses in vitro, these studies were aided by the ability to produce large quantities of L1 protein recombinantly in eukaryotic cells after

HPV vaccination identifying the appropriate open reading frame within the viral genome [7,8]. The expressed L1 protein was shown to spontaneously assemble into virus-like particles (VLPs) with a 72 pentamer structure, closely mimicking the native viral capsid but devoid of any genetic material. Disassembly and reassembly of the VLPs under controlled conditions has been shown to improve the stability and homogeneity of these viral particles [9,10]. Immunization with VLPs, in the presence or absence of adjuvant, produced neutralising antibodies that protect against homologous viral challenge [11,12]. Given promising results in animal trials, two commercial VLP vaccines were licensed, Gardasil® and Cervarix®, which mainly differ in the incorporated HPV type (Gardasil®—HPV 16,18,6,11; Cervarix®—HPV16,18) and the included adjuvant (Gardasil®—aluminium salts; Cervarix®—AS04, containing aluminium salts and a toll-like receptor 4 (TLR4) agonist) [13]. HPV 16 and 18 together are responsible for 70% of cervical cancers while HPV 6 and 11 represent the majority of genital wart infections. Phase III human clinical trials of these vaccines quickly followed, demonstrating the safety of VLPs and a >90% efficacy in protecting against persistent anogenital infections with vaccine strains of HPV in previously uninfected, young (15–26) women [14,15]. The 4-year, end of study data from international, multicentre phase III clinical trials (FUTURE I and II—Gardasil® [16,17]; PATRICIA [18] and CVT [19]—Cervarix®) of these vaccines has been expertly reviewed elsewhere [13]. A key finding was that vaccination of HPV-naive individuals protected them from HPV-associated precancers of the cervix (CIN1-3), vulva (VIN 1-3) and vagina (VaIN 1-3). High titres of neutralising antibodies against the HPV vaccine strains and cross-reactive antibodies against non-vaccine strains have been demonstrated after Gardasil® or Cervarix® administration in humans [20,21]. It has been suggested from animal models that these antibodies either neutralise the ability of HPV to bind to cells or prevent conformational changes to the virion that would enable stable binding to the epithelial cell surface [22,23]. Although neutralising antibodies are strongly correlated with vaccination, the precise mechanism by which the commercial HPV vaccines protect from viral infection requires further investigation. While the prophylactic vaccines were successful in preventing persistent HPV infections and preCopyright © 2015 John Wiley & Sons, Ltd.

55 cancers, there was little benefit for women already infected with HPV prior to enrolment in the studies thus suggesting the need for alternative strategies for a therapeutic vaccine. Prophylactic vaccines rely on blocking viral entry into cervical epithelial cells while therapeutic vaccines must target virus that has become intracellular and will generally involve T-cell-based immunity (Figure 1). In parallel to the development of L1-based prophylactic vaccines, studies on the two oncogenic proteins of HPV, E6 and E7, have proceeded with a view to treating women with existing infection. These viral oncoproteins are continuously expressed within cervical cancer cells and are necessary to maintain the malignant state of the cell [24] thus providing an ideal target for CD8 T-cell-based immunotherapy. The difficulty in developing a therapeutic vaccine is in understanding how best to generate a memory CD8 T-cell response that can be effective at the cervical site. Once established as a malignant lesion, it is likely that cancer-driven immunosuppression is a major barrier to successful immunotherapy. The remainder of this review will examine recent studies on the development and implementation of both prophylactic and therapeutic vaccines. PROPHYLACTIC VACCINES

Effectiveness of vaccine programs Gardasil® and Cervarix® have been available on the market since 2006 and 2009 respectively [25]. Since then, in the USA, over 57 million doses have been administered [26]. The progression from HPV infection to invasive cancer is slow, and accordingly, it is too soon to determine the full effect of vaccination on the incidence of cervical cancer in the general population. Instead, current studies focus on rates of HPV infection or genital warts in the general population as surrogate indicators of vaccine efficacy for clinically diagnosed cervical cancer. A study addressing the effectiveness of Cervarix® in England showed the prevalence of HPV16/18 in women aged 16–24 dropped from 19.1 to 6.5% post introduction of the vaccine [27]. Another study in the UK suggested that Cervarix® and Gardasil® were likely to have a similar clinical impact [28]. After the introduction of Gardasil® for girls in 2009 in Denmark, there were a 67 and 50% drop in the frequency of anogenital warts for female and males respectively in the age group Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

56

S. J. McKee et al.

Figure 1. Proposed mechanism for protection provided by HPV prophylactic and therapeutic vaccines. Prophylactic vaccines (left panel) can generate neutralising anti-capsid antibodies that block the entry of HPV(blue) into the cervical epithelium. Once cells become infected, intracellular virus will liberate peptides that are bound by MHC molecules (green) and displayed at the cell surface (right panel). CD4 and CD8 T cells (red), elicited by therapeutic vaccines, specifically recognise MHC/peptide complexes and initiate direct destruction of the infected cell via perforin/granzyme-mediated apoptosis or secrete cytokines that promote a broader cellular immune response (including macrophages and NK cells) against the cancer

who had received the vaccination [29]. Chlamydia rates stayed the same, suggesting an effect at the level of the vaccine and not changes in sexual behaviour. In Australia, the first country to adopt a government-funded, national vaccine program against HPV in 2007, a decline of 92% in diagnosis of genital warts in young women (aged under 21) was seen in the post vaccine period to 2011 while no significant change was seen in women over 30 years of age[30]. For women under 21 who had received vaccination, no genital wart diagnoses were reported amongst 235 women in 2011. Some initial studies have evidence to suggest that rates of cervical pre-cancers are also declining. Using linear array HPV genotyping test, it was shown that vaccination against HPV could reduce the cumulative incidence of cervical intraepithelial neoplasia grade 2 or higher by 50.6% via direct protection against high-risk HPV and 62.7% via crossprotection against other subtypes [31]. In a large study of 14 085 unvaccinated and 24 871 vaccinated women in Australia, it was found that histological and cytological high-grade abnormalities were Copyright © 2015 John Wiley & Sons, Ltd.

significantly more frequent in unvaccinated compared with vaccinated women within 5 years of vaccine implementation [32]. Other countries such as Japan [33], China [34] and India [35] are beginning to explore the safety, immunogenicity and efficacy of the commercial vaccines. The Gardasil vaccine has also been shown to be safe and effective in young black women from Latin America, Europe and North America [36]. Together, the data suggest that the HPV vaccines are effective in protecting against persistent HPV16/18 infection or genital warts across diverse populations. Although vaccination programs have been implemented in many countries, the high cost of vaccination and the need for three doses over a 6-month period has impeded widespread vaccination in low-resource countries. A cost analysis compared cervical screening, Gardasil® and Cervarix®. It was found that while introduction of either vaccine into Columbia would help to reduce the burden of cervical cancer, at the current price, cervical screening was more cost-effective [37]. One approach to reduce costs and encourage compliance Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination might be to combine the prophylactic HPV vaccine with other existing commercial vaccines. Combined vaccination was found to be safe and did not detract from the immune responses seen with HPV vaccine alone [38]. A reduction in the number of HPV vaccinations might also be of benefit. A study examining women who received one, two or three doses of Cervarix® in the Costa Rica Vaccine Trial suggested that protective efficacy was not reduced even when using a single dose of the vaccine [39]. However, only small numbers of women received a single dose of vaccine in this study suggesting the need for larger trials. In a second study using Cervarix, two versus three doses of vaccine had similar immunogenicity and was well tolerated over a follow-up period of 2 years [40]. Other recent data confirms that two doses are just as effective as three for generating protective immunity [41,42]. One limitation of giving fewer doses may be the impaired development of memory responses although this will require longterm surveillance [43]. One encouraging study suggests that a single dose of bivalent HPV vaccine in the phase III CVT clinical trial lead to durable antibody responses over a 4-year follow-up period [44]. Both Gardasil and Cervarix are administered intramuscularly that, although effective, may not be efficient in attracting and stimulating an immune response designed to operate in the cervix. Intradermal application of either vaccine in humans was more reactogenic than intramuscular delivery and both routes resulted in seroconversion [45]. Further studies will be required to determine if similar protection against HPV infection is induced via this alternative vaccination site. Sublingual administration of Gardasil, which would have the potential to invoke mucosal immunity, actually results in lower titres of serum and vaginal HPV-specific IgG than intramuscular delivery suggesting that alternative mucosal delivery routes might need to be considered [46]. The ability of HPV prophylactic vaccines to induce long-term protection and immune memory will be a key component of public health outcome. Phase III clinical trials have been completed for some years now with participants returning to normal health care systems making long-term tracking more difficult. However, Scandinavian countries such as Finland have national registries that should enable follow-up in these cohorts into the future [47]. One study addressing memory responses Copyright © 2015 John Wiley & Sons, Ltd.

57 looked at patients given a monovalent HPV16 L1 vaccine 8.5 years prior to challenge with the quadravalent HPV vaccine [48]. Serum antibody levels against HPV16 were measured after challenge and were far greater than the antibody levels in a control group that did not receive the monovalent vaccine suggesting the induction of immunological memory. High antibody levels have also been detected in trial recipients of Cervarix 7.3 years after vaccination [49]. The safety profile of both HPV vaccines also continues to be monitored. The vast majority of studies suggest that the vaccines are safe to use in young women and boys [50–52]. A systematic casecontrolled study of young females found no evidence of an increased risk to autoimmune disorder after Gardasil® vaccination [53].

Broad protection against anogenital HPV strains Thanks to its high degree of genomic polymorphism, the HPV family comprises more than 200 subtypes, with around 30 types contributing to cervical malignancies. The two existing prophylactic vaccines fail to cover HPV types that account for 30% of cervical cancers. For example, addition of HPV 33, 45, 31 and 58 would increase vaccine coverage to 85% of cervical cancers [54]. An analysis of the phase III PATRICIA trial suggested that the bivalent Cervarix vaccine gave significant cross protection against HPV 31, 33, 45 and 51[55]. While Gardasil is also cross protective against three of these genotypes, it fails to protect against HPV45 [13]. It appears that Cervarix may generate a greater level of cross protection against nonvaccine genotypes but that cross protection diminishes quickly and is because of a minority of antibodies within the response [26,56]. Vaccinating with more oncogenic HPV subtypes should yield better protection against cervical cancer than reliance on cross protection. Multivalent vaccines (which target a broader range of HPV types) and different approaches to produce immunogenic HPV proteins are being tested [57,58]. A phase III trial of Merck’s V503 nonavalent, HPVL1 VLP vaccine is currently underway with a suggested increased efficacy over Gardasil [59]. This new vaccine targets the two most common HPV types in genital warts and, most importantly, the seven most common oncogenic HPV types found in Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

58 cervical cancer (HPV16, 18, 31, 33, 35, 52, 58) [60]. Multivalent vaccines have the potential to further reduce cervical cancer incidence by up to 30% over the existing commercial vaccines. One alternative to achieve a better protection is vaccination with L2, the minor capsid protein, which has been shown to elicit cross-neutralising antibodies that offer the potential for broad protection from a single antigen (although responses are weaker than with L1 proteins) [61–64]. Indeed, L2 cleavage on its N-terminus by a host-derived furin protease exposes epitopes upon the VLP capsid surface, including a well-defined epitope 17-36 recognised by the cross-neutralising antibody, RG-1 [65]. VLPs containing L1 and L2 are also being investigated as alternative vaccines [66,67] along with co-administration of L1VLPs and L2 protein[68]. Alternative delivery platforms for L1-based and L2-based vaccines are also being investigated. Silica nanoparticles have been suggested to be an effective platform for delivery of immunogenic epitopes from HPV VLP capsid [69] while an Escherichia coli-based vaccine to generate protection against high-risk HPV16/18 was shown to be well tolerated in a phase 1 clinical trial [70]. In one study, a DNA vaccine containing calreticulin linked to HPV E6, E7 and L2 genes was used to successfully induce a neutralising antibody response against the L2 protein [71]. In contrast, a DNA vaccine that expressed L2 protein alone was shown to be immunogenic but did not induce neutralising antibodies that are likely required for prophylactic vaccine efficacy [72]. The discrepancy between the two studies likely reflects the number of vaccinations given to the mice. Optimization of the codon usage within the L1 gene of a DNA vaccine was also shown to improve immunogenecity [73].

Alternative populations to vaccinate With clear evidence now available showing that vaccination of young girls with either Gardasil® or Cervarix® is effective at preventing HPV infections and potentially cervical cancer, focuses are now shifting towards other vulnerable populations. Whether young boys should be vaccinated alongside their female counterparts is now a large area of interest [74,75]. In addition to stopping sexual transmission of HPV, anogenital cancers and genital warts in males represent a significant health burden. A recent study has shown that from a Copyright © 2015 John Wiley & Sons, Ltd.

S. J. McKee et al. cohort men aged 16–20 years old who have sex with men, 39% tested positive for HPV DNA, with 23% testing positive for the vaccine subtypes 6, 11, 16 and 18 [76]. Similarly, a study in South Africa found that 80% of penile precancerous lesions were positive for HPV11 while 62.9% of cancerous lesions were positive for HPV16 with some lesions testing positive for several types [77]. Testing of the quadrivalent Gardasil vaccine in males aged 16–26 indicated >80% efficacy (per protocol population) in protecting against genital lesions and persistent infection with vaccine genotypes [78]. As a consequence of these clinical trials, routine vaccination of both boys and girls now occurs in countries such as Australia, Canada and the USA [79]. Other populations that are traditionally not candidates for vaccination but could benefit from HPV vaccination include the immunosuppressed and pregnant women. In a comparative study of Gardasil® and Cervarix® in 92 HIV+ patients, it was found that both vaccines were well tolerated and immunogenic [80]. Cervarix® generated higher antibody titres against HPV16/18 than Gardasil® in HIV-infected women, although this bias was not seen in men. The feasibility of vaccinating pregnant women or women immediately post-partum has been discussed elsewhere [81,82]. With uptake of the vaccine at only 23% in young adult women in Texas in 2010, it was suggested that a post-partum administration in maternity hospitals would improve vaccine uptake [83]. However, as these women are already sexually active and the therapeutic efficacy of the vaccine is not clear, the success of this approach is still up for debate. THERAPEUTIC VACCINES Clinical trial data clearly show a reduced vaccine efficacy for women who are seropositive or DNA positive for high-risk HPVs and receive either Gardasil® or Cervarix® immunization [17,18]. Consequently, over the next few decades, while herd immunity impacts on HPV prevalence in the community, there will be a clear need for a therapeutic vaccine to treat existing infections and developing cancers. Current treatments for early and advanced cervical cancer such as surgical/cryogenic removal or chemotherapeutic/anti-viral agents (e.g. cisplatin) often fail to prevent recurrent disease and are costly for developing countries [84]. In contrast, the potential for therapeutic vaccines to both attack Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination primary disease and establish systemic immunological memory to deal with disease recurrence/metastasis make this an attractive treatment option. Given the intracellular, non-lytic life cycle of the virus, therapeutic vaccines will likely need to target induction of cytotoxic T cells that recognise cell surface major histocompatibility complex (MHC) molecules containing bound viral peptides derived from the intracellular environment. Once engaged, these T cells are able to induce apoptosis in the infected cell to clear the infection. Both the E6 and E7 proteins of HPV are oncogenes required by the infected cell to maintain a malignant phenotype. Consequently, these proteins are ideal tumour-associated antigens that should provide peptides to the MHC pathway for targeting by cytotoxic T cells. With viral tumour antigens identified, development of therapeutic HPV vaccines has largely addressed delivery methods/vectors and adjuvants that might induce a strong T-cell response; for reviews, refer to [85–88]. Table 1 summarises the various clinical trials of recent therapeutic vaccines. Using a mixture of long peptides based on HPV E6 and E7 sequences emulsified in incomplete Freund’s adjuvant, one phase II study demonstrated a complete disappearance of advanced vulvar intraepithelial neoplasia (VIN) in 47% of patients over a 24 month follow-up after vaccination [89]. VIN has similarity to cervical intraepithelial neoplasia in that both are caused by persistent infection with high-risk HPV types and can progress to invasive carcinoma. Spontaneous regression of grade 3 (advanced) VIN occurs in less than 1.5% of patients suggesting that the long peptide vaccine mediated the therapeutic effect seen in the responding group. Immunotherapy of VIN grades 2 and 3 was also achieved in a clinical trial of a HPV16E6E7L2 fusion protein immunization combined with an inflammatory agent, imiquimod [90]. This approach relies on immune cells stimulated by the vaccination being drawn into the VIN lesion by the local induction of inflammation (imiquimod). Complete regression of VIN as assessed by histology was seen in 63% of patients at week 52 post treatment. Other approaches to immunotherapy in cervical lesions have used chimeric VLPs consisting of the C-terminal sequence of L1/L2 fused with the N-terminus of T-cell epitopes from E6/E7 [91]. Chimeric HPV16 L1E7 VLPs were used in a phase 1 Copyright © 2015 John Wiley & Sons, Ltd.

59 clinical trial on patients with HPV16 positive CIN2/3. Although safe and well tolerated, giving rise to anti-L1 and anti-E7 cytotoxic T cells, the vaccine did not show evidence of clinical improvement [92]. This failure can be partially explained by the presence of pre-existing anti-L1 neutralizing antibodies, generated by previous patient exposure to HPV, which work to clear the vaccine and therefore limit its effectiveness. To circumvent this, the use of heterologous L1 proteins from bovine or canine origin has been envisaged to be used in a prime-boost strategy [93]. Alternatively, a VLP derived from the rabbit hemorrhagic disease virus and modified to express part of the HPVE6 protein overcame complications of pre-existing immunity against HPV L1 proteins and was able to generate an immune response that could reject pre-existing E6expressing subcutaneous tumours [94]. Previously primed CD4 T cells specific for HPV capsid proteins can also generate IL-10 production and inhibit the priming of CD8+ CTL recognising the HPVE7 protein [95,96]. Perhaps surprisingly, the IL-10 producing CD4 T cells in this system require IFN-g signals in order to prevent CD8 T-cell activation [97]. Consequently, the use of anti-IL-10 blocking antibodies to circumvent the suppressive effects of preexisting CD4 T cells should be considered in therapeutic vaccine design. Other delivery vectors for E6 and E7 peptides include Semliki Forest virus (combined with lowdose irradiation) [98], Listeria [99], lentiviruses [100], fusions with heat shock proteins [101], ricin B chain [102], Shiga toxin B subunit [103] and synthetic polymers [104]. Several studies have examined E6 or E7 DNA vaccines combined with various adjuvants [105–107]. Immunization of mice with a mixture of DNA expressing E6/E7 and IL-33 was able to induce regression of a transplantable HPVE6/E7-expressing tumour and generate memory CD8 T cells [108] while an E7 DNA vaccine combined with cyclophosphamide (to reduce regulatory T cells) produced potent antitumour responses [109]. The combination of immunotherapy and chemotherapy is likely to become more prevalent in the future as we begin to understand immunogenic tumour cell death induced by targeted chemotherapeutic drugs [110]. The choice of adjuvant to be used within therapeutic vaccines is likely to be crucial in promoting T-cell responses. Many commercial, prophylactic vaccines are based on alum adjuvants that promote Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

Copyright © 2015 John Wiley & Sons, Ltd. Overlapping long peptide

ISA Pharmaceuticals

13 peptides over the entire sequence of HPV16.E6 (9) and E7 (4)

IL-2

Expressing HPV-16.E6/ E7 + IL-2 (TG4001/ R3484)

HPV-specific T cells

Immunological purpose

ISCOMATRIX Serum antibodies

HPV-specific T cells (not assessed)— neutralizing Ab response to MVA—no IgG to HPV16. E6/E7 Montanide HPV-specific ISA-51, Seppic T-cell and IFNg production (Treg)

N/A

Adj.

Encoding HPV16 target antigens (Lm-LLO-E7 ADXS11-001)

Construct

HPV-16 Recombinant immunotherapeutic HPV-16 E6/

Recombinant modified vaccinia Ankara (MVA)

Transgene/Roche

CSL Ltd

Recombinant Lm-based vaccine

Vaccine

Advaxis, Inc.

Company

Table 1. Five-year overview of HPV clinical trials

Advanced or recurrent cervical carcinoma patients 1b1 cervical cancer patients Grade 3 VIN patients HSIL patients HIV+ males with HPV-

Cervical cancer patients Patients with HPV+ oropharyngeal cancer CIN 2/3 patients Women with recurrent cervical carcinoma CIN2/3 patients CIN2/3 patients

Condition

2012 2009

N/A N/A

2008

N/A

2009

2012

N/A

N/A

IIa [146]

2008

N/A

2008

[145]

II

N/A

[144]

II

NCT01116245 2013 (2010) NCT01266460 2011

II I

II

II

I

[151] [152]

[89] **

[150]

[149]

IIb [147,148]

[143]

I

NCT01598792 2012

[142]*

I

Year Phase Ref 2009

N/A

Trial

60 S. J. McKee et al.

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

Copyright © 2015 John Wiley & Sons, Ltd.

National Institute of Health

VGX Pharma

Eisai

Nventa biopharmaceuticals/ Akela Pharma

Pulsed dendritic Cells

DC pulsed with HPV16/ 18 E7 and Keyhole Limpet Hemocyanin (KLH)

Full length HPV16 E7 Ag fused to Mycobacterium bovis Hsp65 SGN-00101 (HspE7) Encoding Plasmid DNA fragments encapsulated in poly microparticles of HPV16/ 18 E6/E7, (Amolimogene, ZYC101a) Plasmid DNA Expressing HPV-16/ 18 E6/E7 proteins (VGX-3100) + electroporation Heat shock fusion protein-based immunotherapy

E7 fusion protein

N/A

N/A

N/A

HPV-specific T-cell and IFNg production

N/A

HPV16/18 E7specific antibodiesHPV-specific T-cell and IFNg production-no Treg

N/A

N/A

N/A

poly ICLC

N/A

against HPV16 E6E7-HPVspecific T-cell and IFNg production HPV16 E7 IgG level

CIN2/3 patients (with surgical or ablative treatment) CIN 2/3 patients (4 doses) CIN 2/3 and 3 patients Stage Ib and IIa cervical cancer patients

I

N/A

2008

II

I

NCT01188850 2010

NCT01304524 2011

I

NCT00685412 2008

(Continues)

[158]

[157]

[156]

[155]

[153]

NCT00264732 2011 II/III [154] (2005)

I

[116]

II

CIN 2/3 patients

CIN 1-3 patients

[116]

II

NCT00054041 2007 (2004) NCT00075569 2010 (2007) NCT00493545 2008

CIN 3 patients

associated AIN

HPV vaccination 61

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National Cancer Institute

Company

Vaccine

Copyright © 2015 John Wiley & Sons, Ltd. Anti-mitotic chemotherapy and cells infusion

Anti-mitotic chemotherapy

Monoclonal antibody therapy

Plasmid DNA/ heat shock fusion protein

Plasmid DNA

Table 1. (Continued)

[161]

[162]

[163– 165]

II

II

II

Metastatic or NCT01693783 2012 recurrent HPV+ cervical cancer patients NCT01932697 2013 Interferes with Oropharynx/ cell division tonsil/tongue cancer patients HPV-associated NCT01585428 2012 Noncancers (cervical, myeloablative lymphodepleting vulvar, vaginal, penile, anal, and preparative regimen and re- oropharyngeal) infusion of TILs patients in conjunction with highdose aldesleukin Turns off CTLA4 inhibitory immune mechanism

N/A

[160]

I

[159]

NCT00788164 2008

I

Year Phase Ref

CIN 3 patients

Measures of immune response (not specified)

Imiquimod

Trial NCT00988559 2009

Condition CIN 2/3 patients

N/A

Immunological purpose

N/A

Adj.

N/A Docetaxel (Taxotere) + radiation N/A Fludarabine/ Cycolphosphamide + TIL + Aldesleukin (IL-2)

pNGVL4aCRT/E7 (detox) expressing mutated HPV16 E7 fused to calreticulin Prime with pNGVL4aSig/E7 (detox)/ Hsp70, boost with TA-HPV Anti-CTLA4 moAb Ipilimumab

Construct

62 S. J. McKee et al.

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Copyright © 2015 John Wiley & Sons, Ltd. HPV-associated NCT01530997 2011 cancers (head and neck, Oropharyngeal, SCC) patients HPV+ squamous NCT01663259 2010 cell carcinoma of the Oropharynx HPV+ squamous NCT01855451 2013 cell carcinoma of the oropharynx

[166,167]

III [169]

N/A [168]

II

*The first clinical study employing Listeria monocytogenes for the safe control of advanced cervical carcinoma. **An important clinical trial indicating the efficacy of a long-peptide vaccine against HPV 16 E6 and E7 oncoproteins in generating clinical responses in women with HPV 16-associated vulvar intraepithelial neoplasia.

N/A

Cetuximab (Erbitux) moAb + Cisplatin + intensity modulated radiotherapy (IMRT)

(EGFR) inhibitor— interferes with cell division (EGFR) inhibitor— interferes with cell division

Trans-Tasman Radiation Monoclonal Oncology Group (TROG)antibody and Chemoradiotherapy

Interferes with cell division

N/A

N/A

Cisplatin + intensity modulated radiotherapy (IMRT) Cetuximab (Erbitux) moAb

Chemoradiotherapy

University of Michigan Monoclonal Cancer Center antibody therapy

UNC Lineberger Comprehensive Cancer Center

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Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

64 antibody responses and IL-10 secretion that is detrimental for CD8 T-cell responses [95]. ISCOMATRIX is a saponin-based adjuvant used in anti-HPV-related cancer vaccines [111,112] and in prophylactic and therapeutic vaccines against infectious diseases [113]. It is generally safe and well tolerated as well as immunogenic, with a good humoral and cellular response. Its mechanism of action has been recently linked to the targeting of dendritic cells (DCs) in a TLR-independent but MyD88-dependent pathway and the generation of cytokines and chemokines for the activation of both innate and adaptive immunity. ISCOMATRIX has so far been considered as the preferred adjuvant for a strong cytotoxic T-cell response. The TLR family comprises 14 receptors that promote inflammation and cellular immunity. Ligands of these receptors are widely used as adjuvants in vaccines including HPV therapeutic vaccines [114]. Poly ICLC or hiltonol is a poly-L-lysine double-stranded RNA and the ligand of TLR-3 [115]. It is a poly I:C analogue, stabilised against nucleases present in the plasma of humans. Poly ICLC is currently used in a trial to potentiate full-length HPV16 E7 antigen fused to Mycobacterium bovis heat shock protein, inducing modest but detectable levels of HPVspecific immunity associated with a good clinical outcome [116]. Imiquimod is a TLR-7 ligand used to treat skin pathologies. Imiquimod is being clinically used for the treatment of VIN and CIN lesions, leading to their regression. Imiquimod acts on DC and more particularly on Langerhans cells and induces the production of pro-inflammatory cytokines such as IFN-alpha, IL-6, and TNF-alpha [117,118,90]. CpG oligodeoxynucleotide (CpG ODN) is a TLR9 ligand. Pre-clinical studies in mice highlight the potent action of CpG in the eradication of HPVexpressing tumours [119–121]. Polysaccharide adjuvants such as carrageenan, an inexpensive polysaccharide used in a wide spectrum of human use products, including vaginal lubricants, potentially blocks HPV infection in a mouse challenge model [122]. Finally, custom adjuvants that selectively induce the desired response T-cell response are now available. The Finlay Adjuvant Platform, consisting of bacterial outer membrane vesicles and a variety of TLR agonists, is a good example of a versatile vaccine component that can be tailored to promote prophylactic or therapeutic immune responses [123]. Copyright © 2015 John Wiley & Sons, Ltd.

S. J. McKee et al. While inducing T-cell responses is a key focus for second generation vaccine development, the ability of a vaccine to induce T-cell trafficking to the infected tissue and overcome local immunosuppression will be important considerations to the future success of immunotherapy. Using murine skin grafts expressing HPVE7 protein transgenically from a keratinocyte-specific promoter, we have shown that E7 expression results in epithelial hyperplasia and attracts immunosuppressive natural killer T cells (and other immune cells) to the epithelium [124,125]. The skin NKT cells produce chronic levels of IFN-γ that stimulates local myeloid cells to produce indoleamine 2,3-dioxygenase and suppress T-cell immunity [126]. Very little is known about the role of human NKT cells within the cervix of HPV-infected individuals. The suppressive activity of skin-resident NKT cells in transgenic models also contrasts with the immune activating role of systemic NKT cells in transplantable tumours expressing E7 and/or E6 [127,128]. A local cytokine profile consistent with immune regulation was shown to correlate with progression from lowgrade cervical lesions to invasive cervical cancer [129,130]. Regulatory T cells were shown to be increased in patients with cervical dysplasia and persistent HPV infection [131] as well as being isolated from cervical cancer biopsies [132]. The HPVE7 oncoprotein also interferes with antigen processing and presentation to ensure escape from the CD8 T-cell response. While ovalbumin (OVA)expressing epithelial cells were readily killed by OVA-specific CTL, keratinocytes expressing endogenous HPVE7 protein failed to be lysed efficiently by E7-specific CTL and the response to added IFN-g was blunted [133–135]. This suggested that antigen presentation was limited and is consistent with studies showing defects in TAP-1 [136] and the IRF-1 pathway [137–139] in E7-expressing cells. Other strategies that HPV+ cervical cancers use to avoid the immune response have been reviewed elsewhere [140,141]. Together, this data suggests that overcoming the immunosuppressive environment in the malignant cervix will be as important as generating a robust CD8 T-cell response if therapeutic vaccines are to be successful. CONCLUDING REMARKS Prophylactic vaccines against anogenital HPV infections have been highly successful in reducing the burden of cervical pre-cancers and genital Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination

65

warts over the last few years. Continued public health monitoring of the impact of these vaccines will be required into the future given the long latency to invasive cancer and the 30% of cervical cancers not targeted by the current vaccines. Issues such as low vaccination rates, compliance with the vaccine schedule and the introduction of the vaccines into resource-poor countries remain challenges into the future. Provision of the HPV vaccine within existing vaccine programs or the development of a robust therapeutic vaccine to treat women may assist in controlling disease. To address issues with the local tumour microenvironment, a multifaceted vaccine that removes local immunosuppression in addition to promoting T-cell responses might be needed. As our

understanding of tumour immunology and the microenvironment rapidly expands and reliable methods for inducing T-cell responses are identified, a therapeutic HPV vaccine should be achievable within the next decade. CONFLICT OF INTEREST The authors have no competing interests. ACKNOWLEDGEMENTS This work was supported by the National Health and Medical Research Council of Australia (Program grant 569938); National Cancer Institute (grant 5U01CA141583); Cancer Council Queensland; Lions Medical Research Foundation and the Australian Cancer Research Foundation.

REFERENCES 1. Bhat P, Mattarollo SR, Gosmann C, Frazer

L1 and L2 ORF proteins in epithelial cells

14. Paavonen J, Naud P, Salmeron J, et al. Effi-

IH, Leggatt GR. Regulation of immune re-

is sufficient for assembly of HPV virion-

cacy of human papillomavirus (HPV)-16/

sponses to HPV infection and during HPV-

like particles. Virology 1991; 185: 251–257.

18 AS04-adjuvanted vaccine against cervi-

directed immunotherapy. Immunological

8. Kirnbauer R, Booy F, Cheng N, Lowy DR,

cal infection and precancer caused by on-

Schiller JT. Papillomavirus L1 major cap-

cogenic HPV types (PATRICIA): final

2. Leggatt GR, Frazer IH. HPV vaccines: the

sid protein self-assembles into virus-like

analysis of a double-blind, randomised

beginning of the end for cervical cancer.

particles that are highly immunogenic.

study in young women. Lancet 2009; 374:

Current Opinion in Immunology 2007; 19:

Proceedings of the National Academy of Sci-

232–238.

ences of the United States of America 1992;

Reviews 2011; 239: 85–98.

3. Vajdic CM, van Leeuwen MT. Cancer inci-

89: 12180–12184.

301–314. 15. Ault KA. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine

dence and risk factors after solid organ

9. Zhao Q, Allen MJ, Wang Y, et al. Disassem-

on risk of cervical intraepithelial neoplasia

transplantation. International Journal of

bly and reassembly improves morphology

grade 2, grade 3, and adenocarcinoma

Cancer 2009; 125: 1747–1754.

and thermal stability of human papilloma-

in situ: a combined analysis of four

virus

randomised clinical trials. Lancet 2007; 369:

4. Frazer IH, Leggatt GR, Mattarollo SR. Pre-

type

16

virus-like

particles.

vention and treatment of papillomavirus-

Nanomedicine: Nanotechnology, Biology and

related cancers through immunization.

Medicine 2012; 8: 1182–1189.

1861–1868. 16. Dillner J, Kjaer SK, Wheeler CM, et al. Four

10. Zhao Q, Modis Y, High K, et al. Disassem-

year efficacy of prophylactic human papil-

bly and reassembly of human papilloma-

lomavirus quadrivalent vaccine against

5. Mollers M, Vossen JM, Scherpenisse M,

virus virus-like particles produces more

low grade cervical, vulvar, and vaginal

van der Klis FR, Meijer CJ, de Melker HE.

virion-like antibody reactivity. Virology

intraepithelial neoplasia and anogenital

Review: current knowledge on the role of

Journal 2012; 9: 52.

warts: randomised controlled trial. BMJ

Annual Review of Immunology 2011; 29: 111–138.

HPV antibodies after natural infection

11. Breitburd F, Kirnbauer R, Hubbert NL,

and vaccination: implications for monitor-

et al. Immunization with viruslike particles

ing an HPV vaccination programme. Jour-

from

nal of Medical Virology 2013; 85: 1379–1385.

(CRPV) can protect against experimental

6/11/16/18

6. Suzich JA, Ghim SJ, Palmer-Hill FJ, et al.

CRPV infection. Journal of Virology 1995;

associated genital diseases in young

69: 3959–3963.

women. Journal of the National Cancer Insti-

Systemic immunization with papillomavirus L1 protein completely prevents the de-

cottontail

rabbit

papillomavirus

12. Stanley M, Pinto LA, Trimble C. Human

2010; 341: c3493. 17. Munoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)vaccine

on

all

HPV-

tute 2010; 102: 325–339. 18. Lehtinen

M,

Paavonen

J,

Wheeler

velopment of viral mucosal papillomas.

papillomavirus

Proceedings of the National Academy of Sci-

sponses. Vaccine 2012; 30(Suppl 5): F83–87.

CM, et al. Overall efficacy of HPV-16/

ences of the United States of America 1995;

13. Schiller JT, Castellsague X, Garland SM. A

18 AS04-adjuvanted vaccine against

review of clinical trials of human papillo-

grade 3 or greater cervical intraepi-

mavirus prophylactic vaccines. Vaccine

thelial neoplasia: 4-year end-of-study

2012; 30(Suppl 5): F123–138.

analysis of the randomised, double-

92: 11553–11557. 7. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16

Copyright © 2015 John Wiley & Sons, Ltd.

vaccines--immune

re-

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

S. J. McKee et al.

66 blind PATRICIA trial. The Lancet Oncol-

American Society for Clinical Virology 2014;

bivalent and quadrivalent human papillo-

ogy 2012; 13: 89–99.

59: 109–114.

mavirus vaccines from a societal perspec-

19. Kreimer AR, Gonzalez P, Katki HA, et al.

29. Sando

N,

Kofoed

K,

Zachariae

C,

tive in Colombia. PLoS One 2013; 8: e80639.

Efficacy of a bivalent HPV 16/18 vaccine

Fouchard J. A reduced national incidence

against anal HPV 16/18 infection among

of anogenital warts in young danish men

38. Noronha AS, Markowitz LE, Dunne EF.

young women: a nested analysis within

and women after introduction of a na-

Systematic review of human papillomavi-

the Costa Rica Vaccine Trial. The Lancet

tional quadrivalent human papillomavi-

rus

Oncology 2011; 12: 862–870.

rus vaccination programme for young

2014; 32: 2670–2674.

20. Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and

women—an

ecological

study.

Acta

Dermato-Venereologica 2014; 94: 288–292.

vaccine

coadministration.

Vaccine

39. Kreimer AR, Rodriguez AC, Hildesheim A, et al. Proof-of-principle evaluation of the

safety of Cervarix and Gardasil human

30. Ali H, Donovan B, Wand H, et al. Genital

efficacy of fewer than three doses of a biva-

papillomavirus (HPV) cervical cancer vac-

warts in young Australians five years into

lent HPV16/18 vaccine. Journal of the National

cines in healthy women aged 18-45 years.

national human papillomavirus vaccina-

Human Vaccines 2009; 5: 705–719.

tion programme: national surveillance

21. Einstein MH, Baron M, Levin MJ, et al.

data. BMJ 2013; 346: f2032.

Cancer Institute 2011; 103: 1444–1451. 40. Romanowski B, Schwarz TF, Ferguson LM, et al. Immunogenicity and safety of

Comparison of the immunogenicity of

31. Perez-Castro S, Lorenzo-Mahia Y, Inarrea

the HPV-16/18 AS04-adjuvanted vaccine

the human papillomavirus (HPV)-16/18

Fernandez A, et al. Cervical intraepithelial

administered as a 2-dose schedule com-

vaccine and the HPV-6/11/16/18 vaccine

neoplasia grade 2 or worse in Galicia,

pared with the licensed 3-dose schedule:

for oncogenic non-vaccine types HPV-31

Spain: HPV 16 prevalence and vaccina-

results from a randomized study. Human

and HPV-45 in healthy women aged 18-

tion impact. Enfermedades Infecciosas y

45

years.

Human

Vaccines

2011;

7:

Microbiología Clínica 2013; 32: 479–485.

Vaccines 2011; 7: 1374–1386. 41. Lazcano-Ponce E, Stanley M, Munoz N,

32. Gertig DM, Brotherton JM, Budd AC,

et al. Overcoming barriers to HPV vaccina-

22. Day PM, Kines RC, Thompson CD, et al. In

Drennan K, Chappell G, Saville AM. Im-

tion: non-inferiority of antibody response

vivo mechanisms of vaccine-induced pro-

pact of a population-based HPV vaccina-

to human papillomavirus 16/18 vaccine

tection against HPV infection. Cell Host &

tion program on cervical abnormalities: a

in adolescents vaccinated with a two-

Microbe 2010; 8: 260–270.

data linkage study. BMC Medicine 2013;

dose vs. a three-dose schedule at 21

1359–1373.

23. Schiller JT, Day PM, Kines RC. Current un-

11: 227.

months. Vaccine 2014; 32: 725–732.

33. Yoshikawa H, Ebihara K, Tanaka Y, Noda

42. Dobson SR, McNeil S, Dionne M, et al. Im-

fection. Gynecologic Oncology 2010; 118:

K. Efficacy of quadrivalent human papillo-

munogenicity of 2 doses of HPV vaccine in

S12–17.

mavirus (types 6, 11, 16 and 18) vaccine

younger adolescents vs 3 doses in young

24. zur Hausen H. Immortalization of human

(GARDASIL) in Japanese women aged 18-

women: a randomized clinical trial. JAMA

cells and their malignant conversion by

26 years. Cancer Science 2013; 104: 465–472.

high risk human papillomavirus geno-

34. Li R, Li Y, Radley D, et al. Safety and im-

43. Smolen KK, Gelinas L, Franzen L, et al.

types. Seminars in Cancer Biology 1999; 9:

munogenicity of a vaccine targeting hu-

Age of recipient and number of doses dif-

405–411.

man papillomavirus types 6, 11, 16 and

ferentially impact human B and T cell im-

18: a randomized, double-blind, placebo-

mune

controlled trial in Chinese males and fe-

vaccination. Vaccine 2012; 30: 3572–3579.

derstanding of the mechanism of HPV in-

25. Markowitz LE, Tsu V, Deeks SL, et al. Human papillomavirus

vaccine

introduction--the

first five years. Vaccine 2012; 30(Suppl 5):

males. Vaccine 2012; 30: 4284–4291.

2013; 309: 1793–1802.

memory

responses

to

HPV

44. Safaeian M, Porras C, Pan Y, et al. Durable

35. Bhatla N, Suri V, Basu P, et al. Immunogenic-

antibody responses following one dose of

26. Malagon T, Drolet M, Boily MC, et al.

ity and safety of human papillomavirus-16/

the bivalent human papillomavirus L1

Cross-protective efficacy of two human

18 AS04-adjuvanted cervical cancer vaccine

virus-like particle vaccine in the Costa

papillomavirus vaccines: a systematic re-

in healthy Indian women. The Journal of

Rica Vaccine Trial. Cancer Prevention Re-

view and meta-analysis. The Lancet Infec-

Obstetrics and Gynaecology Research 2010; 36:

tious Diseases 2012; 12: 781–789.

123–132.

F139–148.

search 2013; 6: 1242–1250. 45. Nelson EA, Lam HS, Choi KC, et al. A pilot

27. Mesher D, Soldan K, Howell-Jones R, et al.

36. Clark LR, Myers ER, Huh W, et al. Clinical

randomized study to assess immunoge-

Reduction in HPV 16/18 prevalence in

trial experience with prophylactic human

nicity, reactogenicity, safety and tolerabil-

sexually active young women following

papillomavirus 6/11/16/18 vaccine in

ity

the introduction of HPV immunisation in

young black women. The Journal of Adoles-

vaccines

cent Health: Official Publication of the Society

and intradermally to females aged 18-26

England. Vaccine 2013; 32: 26–32. 28. Hibbitts S, Tristram A, Beer H, et al. UK

for Adolescent Medicine 2013; 52: 322–329.

of

two

human

papillomavirus

administered

intramuscularly

years. Vaccine 2013; 31: 3452–3460.

population based study to predict impact

37. Aponte-Gonzalez J, Fajardo-Bernal L, Diaz

46. Huo Z, Bissett SL, Giemza R, Beddows S,

of HPV vaccination. Journal of Clinical Vi-

J, Eslava-Schmalbach J, Gamboa O, Hay

Oeser C, Lewis DJ. Systemic and mucosal

rology: The Official Publication of the Pan

JW. Cost-effectiveness analysis of the

immune

Copyright © 2015 John Wiley & Sons, Ltd.

responses

to

sublingual

or

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination

67

intramuscular human papilloma virus an-

Alpha-9 inter-type specificities. Vaccine

tigens in healthy female volunteers. PLoS

2014; 32: 1139–1146.

One 2012; 7: e33736.

papillomavirus vaccines. Journal of Virology 2009; 83: 10085–10095.

57. Ahmed AI, Bissett SL, Beddows S. Amino

68. Jagu S, Kwak K, Garcea RL, Roden RB.

47. Clayton J. Clinical approval: trials of an

acid sequence diversity of the major hu-

Vaccination with multimeric L2 fusion

anticancer jab. Nature 2012; 488: S4–6.

man papillomavirus capsid protein: impli-

protein and L1 VLP or capsomeres to

48. Rowhani-Rahbar A, Alvarez FB, Bryan JT,

cations for current and next generation

broaden protection against HPV infection.

et al. Evidence of immune memory 8.5

vaccines. Infection, Genetics and Evolution

years following administration of a pro-

2013; 18: 151–159.

Vaccine 2010; 28: 4478–4486. 69. Singharoy A, Polavarapu A, Joshi H, Baik

phylactic human papillomavirus type 16

58. Schiller JT, Nardelli-Haefliger D. Chapter

MH, Ortoleva P. Epitope fluctuations in

vaccine. Journal of Clinical Virology: The Of-

17: second generation HPV vaccines to

the human papillomavirus are under

ficial Publication of the Pan American Society

prevent cervical cancer. Vaccine 2006; 24

dynamic allosteric control: a computa-

for Clinical Virology 2012; 53: 239–243.

(Suppl 3): S3/147–153.

tional evaluation of a new vaccine design

49. Schwarz TF. Clinical update of the AS04adjuvanted human papillomavirus-16/18 cervical cancer vaccine, Cervarix. Advances in Therapy 2009; 26: 983–998.

59. HPV vaccine works against nine viral types. Cancer Discovery 2014; 4: OF2.

Society 2013; 135: 18458–18468.

60. Wang JW, Roden RB. Virus-like particles for

50. Macartney KK, Chiu C, Georgousakis M,

the

prevention

papillomavirus-associated

Brotherton JM. Safety of human papillo-

Expert

Review

mavirus vaccines: a review. Drug Safety:

129–141.

of

of

strategy. Journal of the American Chemical 70. Hu YM, Huang SJ, Chu K, et al. Safety of

human

an Escherichia coli-expressed bivalent hu-

malignancies.

man papillomavirus (types 16 and 18) L1

Vaccines

2013;

12:

virus-like particle vaccine: An open-label phase I clinical trial. Human Vaccines & Immunotherapeutics 2014; 10: 469–475.

An International Journal of Medical Toxicol-

61. Gambhira R, Gravitt PE, Bossis I, Stern PL,

ogy and Drug Experience 2013; 36: 393–412.

Viscidi RP, Roden RB. Vaccination of

71. Kim D, Gambhira R, Karanam B, et al.

51. Luna J, Plata M, Gonzalez M, et al. Long-

healthy volunteers with human papillo-

Generation and characterization of a pre-

term follow-up observation of the safety,

mavirus type 16 L2E7E6 fusion protein in-

ventive and therapeutic HPV DNA vac-

immunogenicity,

of

duces serum antibody that neutralizes

gardasil in adult women. PLoS One 2013;

across papillomavirus species. Cancer Re-

and

effectiveness

search 2006; 66: 11120–11124.

8: e83431.

cine. Vaccine 2008; 26: 351–360. 72. Hitzeroth, II, Passmore JA, Shephard E, et al. Immunogenicity of an HPV-16 L2

52. Moreira ED, Jr., Palefsky JM, Giuliano AR,

62. Tyler M, Tumban E, Chackerian B. Second-

DNA vaccine. Vaccine 2009; 27: 6432–6434.

et al. Safety and reactogenicity of a quadri-

generation prophylactic HPV vaccines:

73. Liu WJ, Zhao KN, Gao FG, Leggatt GR,

valent human papillomavirus (types 6, 11,

successes and challenges. Expert Review of

Fernando GJ, Frazer IH. Polynucleotide vi-

16, 18) L1 viral-like-particle vaccine in

Vaccines 2014; 13: 247–255.

ral vaccines: codon optimisation and ubiq-

older adolescents and young adults. Hu-

63. Tumban E, Peabody J, Peabody DS,

uitin conjugation enhances prophylactic

Chackerian B. A universal virus-like

and therapeutic efficacy. Vaccine 2001; 20:

D,

particle-based vaccine for human papillo-

862–869.

Godeau B, et al. Autoimmune disorders

mavirus: longevity of protection and role

and quadrivalent human papillomavirus

of endogenous and exogenous adjuvants.

vaccination of young female subjects. Jour-

Vaccine 2013; 31: 4647–4654.

man Vaccines 2011; 7: 768–775. 53. Grimaldi-Bensouda

L,

Guillemot

74. Roehr B. US committee recommends HPV vaccine for boys. BMJ 2011; 343: d7068. 75. Moreira ED, Jr., Giuliano AR, Palefsky J,

nal of Internal Medicine 2014; 275: 398–408.

64. Jagu S, Kwak K, Karanam B, et al. Optimi-

et al. Incidence, Clearance and Progression

54. Schiffman M, Castle PE, Jeronimo J,

zation of multimeric human papillomavi-

to Disease of Genital Human Papillomavi-

Rodriguez AC, Wacholder S. Human pap-

rus L2 vaccines. PLoS One 2013; 8: e55538.

rus Infection in Heterosexual Men. The

illomavirus and cervical cancer. Lancet

65. Schellenbacher C, Kwak K, Fink D,

Journal of Infectious Diseases 2014; 210:

2007; 370: 890–907.

et al. Efficacy of RG1-VLP vaccination

192–199.

55. Wheeler CM, Castellsague X, Garland SM,

against infections with genital and cu-

76. Zou H, Tabrizi SN, Grulich AE, et al.

et al. Cross-protective efficacy of HPV-16/

taneous human papillomaviruses. The

Early acquisition of anogenital human

18 AS04-adjuvanted vaccine against cervi-

Journal of Investigative Dermatology 2013;

papillomavirus among teenage men who

cal infection and precancer caused by non-

133: 2706–2713.

have sex with men. Journal of Infectious Diseases 2014; 209: 642–651.

vaccine oncogenic HPV types: 4-year end-

66. McGrath M, de Villiers GK, Shephard E,

of-study analysis of the randomised,

Hitzeroth II, Rybicki EP. Development of

77. Lebelo RL, Boulet G, Nkosi CM, Bida

double-blind PATRICIA trial. The Lancet

human papillomavirus chimaeric L1/L2

MN, Bogers JP, Mphahlele MJ. Diversity

Oncology 2012; 13: 100–110.

candidate vaccines. Archives of Virology

of HPV types in cancerous and pre-

2013; 158: 2079–2088.

cancerous penile lesions of South African

56. Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibod-

67. Schellenbacher C, Roden R, Kirnbauer R.

men: Implications for future HPV vacci-

ies elicited by the Cervarix human pap-

Chimeric L1-L2 virus-like particles as

nation strategies. Journal of Medical Virol-

illomavirus vaccine display a range of

potential

ogy 2014; 86: 257–265.

Copyright © 2015 John Wiley & Sons, Ltd.

broad-spectrum

human

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

S. J. McKee et al.

68 78. Giuliano AR, Palefsky JM, Goldstone S,

for vulvar intraepithelial neoplasia. The

99. Rothman J, Paterson Y. Live-attenuated

et al. Efficacy of quadrivalent HPV vaccine

New England Journal of Medicine 2009; 361:

Listeria-based immunotherapy. Expert Re-

against HPV Infection and disease in

1838–1847.

males. The New England Journal of Medicine 2011; 364: 401–411. 79. Stanley M. Perspective: Vaccinate boys too. Nature 2012; 488: S10. 80. Toft L, Storgaard M, Muller M, et al. Comparison

of

the

immunogenicity

and

view of Vaccines 2013; 12: 493–504.

90. Daayana S, Elkord E, Winters U, et al.

100. Grasso F, Negri DR, Mochi S, et al. Success-

Phase II trial of imiquimod and HPV ther-

ful therapeutic vaccination with integrase

apeutic vaccination in patients with vulval

defective

intraepithelial neoplasia. British Journal of

nononcogenic human papillomavirus E7

Cancer 2010; 102: 1129–1136.

protein. International Journal of Cancer

91. Monroy-Garcia

A,

Gomez-Lim

MA,

lentiviral

vector

expressing

2013; 132: 335–344.

reactogenicity of cervarix and gardasil hu-

Weiss-Steider B, et al. Immunization with

101. Zong J, Wang C, Liu B, et al. Human hsp70

man papillomavirus vaccines in HIV-

an HPV-16 L1-based chimeric virus-like

and HPV16 oE7 fusion protein vaccine in-

infected adults: a randomized, double-

particle containing HPV-16 E6 and E7 epi-

duces an effective antitumor efficacy. On-

blind clinical trial. The Journal of Infectious

topes elicits long-lasting prophylactic and

cology Reports 2013; 30: 407–412.

Diseases 2014; 209: 1165–1173.

therapeutic efficacy in an HPV-16 tumor

81. Berenson AB, Patel PR, Barrett AD. Is administration of the HPV vaccine during pregnancy feasible in the future? Expert

102. Sadraeian

M,

Rasoul-Amini

S,

mice model. Archives of Virology 2014; 159:

Mansoorkhani MJ, Mohkam M, Ghoshoon

291–305.

MB, Ghasemi Y. Induction of antitumor

92. Kaufmann AM, Nieland JD, Jochmus I,

immunity against cervical cancer by pro-

et al. Vaccination trial with HPV16 L1E7

tein HPV-16 E7 in fusion with ricin B chain

chimeric virus-like particles in women suf-

in tumor-bearing mice. International Jour-

man papillomavirus (HPV) 6/11-infected

fering

cervical

nal of Gynecological Cancer: Official Journal

pregnant women with the quadrivalent

intraepithelial neoplasia (CIN 2/3). Inter-

of the International Gynecological Cancer So-

HPV vaccine to prevent juvenile-onset la-

national Journal of Cancer 2007; 121:

ryngeal papilloma. Journal of Infectious Dis-

2794–2800.

Review of Vaccines 2014; 13: 213–219. 82. Shah KV. A case for immunization of hu-

eases 2014; 209: 1307–1309.

from

high

grade

ciety 2013; 23: 809–814. 103. Sadraeian M, Khoshnood Mansoorkhani

93. Da Silva DM, Schiller JT, Kast WM. Heter-

MJ,

Mohkam

M,

Rasoul-Amini

S,

83. Berenson AB, Male E, Lee TG, et al.

ologous boosting increases immunogenic-

Hesaraki M, Ghasemi Y. Prevention and

Assessing the need for and acceptability of

ity of chimeric papillomavirus virus-like

inhibition of TC-1 cell growth in tumor

a free-of-charge postpartum HPV vaccina-

particle

tion program. American Journal of Obstetrics

3219–3227.

vaccines.

Vaccine

2003;

21:

94. Jemon K, Young V, Wilson M, et al. An en-

and Gynecology 2014; 210: 213 e211–217.

bearing mice by HPV16 E7 protein in fusion with shiga toxin b-subunit from shigella dysenteriae. Cell Journal 2013; 15: 176–181.

84. Diaz-Padilla I, Monk BJ, Mackay HJ,

hanced heterologous virus-like particle for

Oaknin A. Treatment of metastatic cervical

human papillomavirus type 16 tumour

104. Liu TY, Hussein WM, Jia Z, et al. Self-

immunotherapy. PLoS One 2013; 8: e66866.

adjuvanting polymer-peptide conjugates

95. Liu XS, Xu Y, Hardy L, et al. IL-10 medi-

as therapeutic vaccine candidates against

Oncology/Hematology 2013; 85: 303–314.

ates suppression of the CD8 T cell IFN-

cervical cancer. Biomacromolecules 2013;

85. Hung CF, Ma B, Monie A, Tsen SW, Wu

gamma response to a novel viral epitope

TC. Therapeutic human papillomavirus

in a primed host. Journal of Immunology

cancer:

future

targeted

agents.

directions Critical

involving Reviews

in

vaccines: current clinical trials and future directions. Expert Opinion on Biological Therapy 2008; 8: 421–439.

2003; 171: 4765–4772. 96. Liu XS, Dyer J, Leggatt GR, et al. Overcom-

14: 2798–2806. 105. Kim H, Kwon B, Sin JI. Combined stimulation of IL-2 and 4-1BB receptors augments the antitumor activity of E7 DNA vaccines

ing original antigenic sin to generate new

by increasing ag-specific CTL responses.

86. Lin K, Doolan K, Hung CF, Wu TC. Per-

CD8 T cell IFN-gamma responses in an

PLoS One 2013; 8: e83765.

spectives for preventive and therapeutic

antigen-experienced host. Journal of Immu-

HPV vaccines. Journal of the Formosan Med-

nology 2006; 177: 2873–2879.

ical Association 2010; 109: 4–24.

106. Han KT, Sin JI. DNA vaccines targeting human

papillomavirus-associated

dis-

97. Liu XS, Leerberg J, MacDonald K, Leggatt

eases: progresses in animal and clinical

87. Ma B, Maraj B, Tran NP, et al. Emerging

GR, Frazer IH. IFN-gamma promotes gen-

studies. Clinical and Experimental Vaccine

human papillomavirus vaccines. Expert

eration of IL-10 secreting CD4+ T cells that

Opinion on Emerging Drugs 2012; 17:

suppress generation of CD8 responses in

107. Diniz MO, Cariri FA, Aps LR, Ferreira

469–492.

an antigen-experienced host. Journal of Im-

LC. Enhanced therapeutic effects con-

munology 2009; 183: 51–58.

ferred by an experimental DNA vaccine

88. Bergot AS, Kassianos A, Frazer IH, Mittal

Research 2013; 2: 106–114.

D. New approaches to immunotherapy

98. Draghiciu O, Walczak M, Hoogeboom BN,

targeting human papillomavirus-induced

for HPV associated cancers. Cancers (Basel)

et al. Therapeutic immunization and local

tumors. Human Gene Therapy 2013; 24:

2011; 3: 3461–3495.

low-dose tumor irradiation, a reinforcing

89. Kenter GG, Welters MJ, Valentijn AR, et al. Vaccination against HPV-16 oncoproteins

combination. International Journal of Cancer 2014; 134: 859–872.

Copyright © 2015 John Wiley & Sons, Ltd.

861–870. 108. Villarreal D, Wise MC, Walters JN, et al. Alarmin IL-33 acts as an immunoadjuvant

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination

69

to enhance antigen-specific tumor immu-

antitumor immunity induced by therapeu-

127. Kim D, Hung CF, Wu TC, Park YM. DNA

nity. Cancer Research 2014; 74: 1789–1800.

tic HPV DNA vaccination. Journal of Bio-

vaccine with alpha-galactosylceramide at

medical Science 2010; 17: 32.

prime phase enhances anti-tumor immu-

109. Peng S, Lyford-Pike S, Akpeng B, et al. Low-dose

cyclophosphamide

adminis-

119. Daftarian P, Mansour M, Benoit AC, et al. HPV

16-

after

boosting

with

antigen-

antitumor effects of a therapeutic HPV

expressing tumors by a single administra-

vaccine. Cancer Immunology, Immunother-

tion of a vaccine composed of a liposome-

128. Stewart TJ, Smyth MJ, Fernando GJ, Frazer

apy: CII 2013; 62: 171–182.

encapsulated CTL-T helper fusion peptide

IH, Leggatt GR. Inhibition of early tumor

in a water-in-oil emulsion. Vaccine 2006;

growth requires J alpha 18-positive (natu-

24: 5235–5244.

ral killer T) cells. Cancer Research 2003; 63:

The need for improvement of the treat-

established

expressing dendritic cells. Vaccine 2010;

Eradication

110. van Meir H, Kenter GG, Burggraaf J, et al.

of

nity

tered as daily or single dose enhances the

28: 7297–7305.

ment of advanced and metastatic cervical

120. Wang HL, Xu H, Lu WH, Zhu L,

cancer, the rationale for combined chemo-

Yu YH, Hong FZ. In vitro and in vivo

129. Peghini BC, Abdalla DR, Barcelos AC,

immunotherapy. Anti-Cancer Agents in Me-

evaluations of human papillomavirus

Teodoro L, Murta EF, Michelin MA. Local

dicinal Chemistry 2014; 14: 190–203.

type 16 (HPV16)-derived peptide-loaded

cytokine profiles of patients with cervical

dendritic

intraepithelial and invasive neoplasia. Hu-

111. Frazer IH, Quinn M, Nicklin JL, et al. Phase

cells

(DCs)

with

a

CpG

3058–3060.

man Immunology 2012; 73: 920–926.

1 study of HPV16-specific immunotherapy

oligodeoxynucleotide (CpG-ODN) adju-

with

and

vant as tumor vaccines for immuno-

130. Scott ME, Ma Y, Kuzmich L, Moscicki AB.

ISCOMATRIX adjuvant in women with

therapy of cervical cancer. Archives of

Diminished IFN-gamma and IL-10 and el-

cervical intraepithelial neoplasia. Vaccine

Gynecology

evated Foxp3 mRNA expression in the cer-

2004; 23: 172–181.

155–162.

E6E7

fusion

protein

and

Obstetrics

2014;

289:

vix are associated with CIN 2 or 3. International Journal of Cancer 2009; 124:

112. Stewart TJ, Drane D, Malliaros J, et al.

121. Zwaveling S, Ferreira Mota SC, Nouta J,

ISCOMATRIX adjuvant: an adjuvant suit-

et al. Established human papillomavirus

able for use in anticancer vaccines. Vaccine

type 16-expressing tumors are effectively

2004; 22: 3738–3743.

eradicated following vaccination with

CD4(+)CD25hi

long peptides. Journal of Immunology 2002;

quency correlates with persistence of hu-

169: 350–358.

man papillomavirus type 16 and T

113. Morelli AB, Becher D, Koernig S, Silva A, Drane D, Maraskovsky E. ISCOMATRIX:

1379–1383. 131. Molling JW, de Gruijl TD, Glim J, et al. regulatory

T-cell

fre-

a novel adjuvant for use in prophylactic

122. Burchell AN, Winer RL, de Sanjose S,

helper cell responses in patients with cer-

and therapeutic vaccines against infectious

Franco EL. Chapter 6: Epidemiology and

vical intraepithelial neoplasia. Interna-

diseases. Journal of Medical Microbiology

transmission dynamics of genital HPV in-

tional

2012; 61: 935–943.

fection. Vaccine 2006; 24(Suppl 3): S3/

1749–1755.

114. Domingos-Pereira S, Decrausaz L, Derre L,

52–61.

Journal

of

Cancer

2007;

121:

132. van der Burg SH, Piersma SJ, de Jong A,

et al. Intravaginal TLR agonists increase lo-

123. Perez O, Romeu B, Cabrera O, et al. Adju-

et al. Association of cervical cancer with

cal vaccine-specific CD8 T cells and human

vants are key factors for the development

the presence of CD4+ regulatory T cells

papillomavirus-associated

genital-tumor

of future vaccines: lessons from the finlay

specific for human papillomavirus anti-

regression in mice. Mucosal Immunology

adjuvant platform. Frontiers in Immunology

gens. Proceedings of the National Academy

2013; 6: 393–404.

2013; 4: 407.

of Sciences of the United States of America

115. Stahl-Hennig C, Eisenblatter M, Jasny E,

124. Mattarollo SR, Rahimpour A, Choyce A,

et al. Synthetic double-stranded RNAs are

Godfrey DI, Leggatt GR, Frazer IH. Invari-

adjuvants for the induction of T helper 1

ant NKT cells in hyperplastic skin induce a

Keratinocytes efficiently process endoge-

and humoral immune responses to human

local immune suppressive environment by

nous antigens for cytotoxic T-cell mediated

papillomavirus in rhesus macaques. PLoS

IFN-gamma production. Journal of Immu-

lysis. Experimental Dermatology 2009; 18:

Pathogens 2009; 5: e1000373.

nology 2010; 184: 1242–1250.

2007; 104: 12087–12092. 133. Zhou

F,

Frazer

IH,

Leggatt

GR.

1053–1059.

116. Van Doorslaer K, Reimers LL, Studentsov

125. Choyce A, Yong M, Narayan S, et al. Ex-

134. Zhou F, Leggatt GR, Frazer IH. Human

YY, Einstein MH, Burk RD. Serological re-

pression of a single, viral oncoprotein in

papillomavirus 16 E7 protein inhibits

sponse to an HPV16 E7 based therapeutic

skin epithelium is sufficient to recruit lym-

interferon-gamma-mediated enhancement

vaccine in women with high-grade cervi-

phocytes. PLoS One 2013; 8: e57798.

of keratinocyte antigen processing and T-

cal dysplasia. Gynecologic Oncology 2010;

126. Mittal D, Kassianos AJ, Tran LS, et al. Indoleamine

116: 208–212.

2,3-dioxygenase

activity

cell lysis. The FEBS Journal 2011; 278: 955–963.

117. Bilu D, Sauder DN. Imiquimod: modes of

contributes to local immune suppression

135. Leggatt GR, Dunn LA, De Kluyver RL,

action. British Journal of Dermatology 2003;

in the skin expressing human papillo-

Stewart T, Frazer IH. Interferon-gamma

149(Suppl 66): 5–8.

mavirus oncoprotein e7. The Journal of

enhances cytotoxic T lymphocyte recogni-

Investigative

tion

118. Chuang CM, Monie A, Hung CF, Wu TC. Treatment

with

imiquimod

enhances

2686–2694.

Copyright © 2015 John Wiley & Sons, Ltd.

Dermatology

2013;

133:

of

keratinocytes

endogenous without

peptide

in

lowering

the

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

S. J. McKee et al.

70 requirement for surface peptide. Immunol-

treatment of persistent or recurrent squa-

HPV-16

ogy and Cell Biology 2002; 80: 415–424.

mous or non-squamous cell carcinoma of

positive participants with oncogenic HPV

the cervix. ClinicalTrials.gov.

infection of the anus. Journal of Acquired

136. Fowler NL, Frazer IH. Mutations in TAP genes are common in cervical carcinomas.

Gynecologic

Oncology

2004;

92:

146. Transgene and roche modify the clinical development programme for their HPVtargeted immunotherapy TG4001/R3484.

914–921.

therapeutic

vaccine

in

HIV-

Immune Deficiency Syndromes 2009; 52: 371–381. 153. A multicenter, nonrandomized, open-label

137. Park JS, Kim EJ, Kwon HJ, Hwang ES,

http://www.transgene.fr/index.php?

phase 1 safety study of HspE7 and poly-

Namkoong SE, Um SJ. Inactivation of in-

option=com_content&view=article&i-

ICLC administered concomitantly in cervi-

terferon regulatory factor-1 tumor sup-

d=33%3Apressreleases&catid=7%

cal intraepithelial neoplasia (CIN) subjects.

pressor protein by HPV E7 oncoprotein.

3Ainvestors-media&Itemid=56&lang=en

Implication for the E7-mediated immune

[07/01/2014].

ClinicalTrials.gov. 154. Matijevic M, Hedley ML, Urban RG, Chicz

evasion mechanism in cervical carcinogen-

147. Transgene reports randomized phase 2b

RM, Lajoie C, Luby TM. Immunization

esis. The Journal of Biological Chemistry

data with its therapeutic HPV vaccine

with a poly (lactide co-glycolide) encapsu-

2000; 275: 6764–6769.

TG4001

CIN2/3

lated plasmid DNA expressing antigenic

intraepithelial cervical neoplasia. 2012.

regions of HPV 16 and 18 results in an in-

papillomavirus type 16 E7 impairs the ac-

http://www.transgene.fr/?

crease in the precursor frequency of T cells

tivation

option=com_content&view=article&i-

that respond to epitopes from HPV 16, 18, 6

138. Perea SE, Massimi P, Banks L. Human of

the

interferon

regulatory

factor-1. International Journal of Molecular

in

women

with

d=59&Itemid=73&lang=en [07/01/2014]. 148. Brun JL, Dalstein V, Leveque J, et al. Re-

Medicine 2000; 5: 661–666.

cervical

to evaluate the safety, tolerability and im-

mavirus 16-encoded E7 protein inhibits

intraepithelial neoplasia with TG4001

munogenicity of human papillomavirus

IFN-gamma-mediated MHC class I anti-

targeted immunotherapy. American Journal

(HPV) DNA plasmid (VGX-3100) + elec-

gen presentation and CTL-induced lysis

of Obstetrics and Gynecology 2011; 204: 169

troporation (EP) in adult females post sur-

by blocking IRF-1 expression in mouse

e161–168.

gical or ablative treatment of grade 2 or 3

139. Zhou F, Chen J, Zhao KN. Human papillo-

keratinocytes. The Journal of General Virology 2013; 94: 2504–2514.

gression

of

high-grade

and 11. Cellular Immunology 2011; 270: 62–69. 155. Phase I open label, dose escalation study

149. Kenter GG, Welters MJ, Valentijn AR, et al. Phase I immunotherapeutic trial

cervical intraepithelial neoplasia (CIN). ClinicalTrials.gov.

140. Frazer IH, Thomas R, Zhou J, et al. Poten-

with long peptides spanning the E6

156. Phase I, Open-label Study to Evaluate the

tial strategies utilised by papillomavirus

and E7 sequences of high-risk human

Safety, Tolerability and Immunogenicity

to evade host immunity. Immunological Re-

papillomavirus 16 in end-stage cervical

of a Fourth Dose of Human Papillomavi-

views 1999; 168: 131–142.

cancer patients shows low toxicity and

rus (HPV) DNA Plasmid (VGX-3100) +

141. Tindle RW. Immune evasion in human

robust immunogenicity. Clinical Cancer

Electroporation (EP) in Adult Females Pre-

papillomavirus-associated cervical cancer.

Research: An Official Journal of the Ameri-

viously

Nature Reviews. Cancer 2002; 2: 59–65.

can Association for Cancer Research 2008;

ClinicalTrials.gov.

142. Maciag PC, Radulovic S, Rothman J. The

Immunized

With

VGX-3100.

157. Phase II placebo controlled study of VGX-

14: 169–177.

first clinical use of a live-attenuated

150. Welters MJ, Kenter GG, Piersma SJ, et al.

3100, (HPV16 E6/E7, HPV18 E6/E7 DNA

Listeria monocytogenes vaccine: a phase I

Induction of tumor-specific CD4+ and

Vaccine) delivered IM followed by electro-

safety study of Lm-LLO-E7 in patients

CD8+ T-cell immunity in cervical cancer

poration with cellectra-5P for the treat-

with advanced carcinoma of the cervix.

patients by a human papillomavirus type

ment of biopsy-proven CIN 2/3 or CIN 3

Vaccine 2009; 27: 3975–3983.

16 E6 and E7 long peptides vaccine. Clini-

with

143. REALISTIC: A phase I, dose escalation trial

cal Cancer Research: An Official Journal of

ClinicalTrials.gov.

of recombinant listeria monocytogenes

the American Association for Cancer Research

(Lm)-based

2008; 14: 178–187.

vaccine

encoding

human

documented

HPV

16

or

18.:

158. Santin AD, Bellone S, Palmieri M, et al. Human papillomavirus type 16 and 18 E7-

papilloma virus genotype 16 target anti-

151. de Vos van Steenwijk PJ, Ramwadhdoebe

pulsed dendritic cell vaccination of stage

gens (ADXS11-001) in patients with HPV-

TH, Lowik MJ, et al. A placebo-controlled

IB or IIA cervical cancer patients: a phase

16 +ve oropharyngeal carcinoma safety.

randomized

ClinicalTrials.gov.

peptide vaccination study in women with

144. Randomized, single blind, placebo con-

synthetic

I escalating-dose trial. Journal of Virology 2008; 82: 1968–1979.

squamous

159. A pilot study of pnGVL4a-CRT/E7 (De-

intraepithelial lesions. Cancer Immunology,

tox) for the treatment of patients with

of ADXS11-001 for the treatment of cervi-

Immunotherapy: CII 2012; 61: 1485–1492.

HPV16+ cervical intraepithelial neoplasia

ClinicalTrials.gov.

cervical

long-

trolled phase 2 study to assess the safety cal intraepithelial neoplasia grade 2/3.

high-grade

HPV16

152. Anderson JS, Hoy J, Hillman R, et al. A randomized,

2/3 (CIN2/3). ClinicalTrials.gov.

dose-

160. A phase I efficacy and safety study of

145. A phase II evaluation of ADXS11-001

escalation study to determine the safety,

HPV16-specific therapeutic DNA-vaccinia

(NSC 752718, BB-IND#13,712) in the

tolerability, and immunogenicity of an

vaccination in combination with topical

Copyright © 2015 John Wiley & Sons, Ltd.

placebo-controlled,

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv

HPV vaccination

71

imiquimod, in patients with HPV16+ high grade

cervical

dysplasia

(CIN3).

164. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising

related oropharyngeal squamous cell carcinoma. ClinicalTrials.gov.

oropharyngeal cancer incidence in the

167. Ang KK, Harris J, Wheeler R, et al. Human

161. A phase 2 study of ipilimumab in women

United States. Journal of Clinical Oncol-

papillomavirus and survival of patients

with metastatic or recurrent HPV-related cer-

ogy: Official Journal of the American Soci-

with

vical carcinoma of either squamous cell or ad-

ety

England Journal of Medicine 2010; 363: 24–35.

ClinicalTrials.gov.

enocarcinoma histologies. ClinicalTrials.gov.

of

Clinical

Oncology

2011;

29:

4294–4301.

oropharyngeal

cancer.

The

New

168. Reduced-intensity therapy for advanced

adjuvant

165. Rosenberg SA, Yang JC, Sherry RM, et al.

oropharyngeal cancer in non-smoking hu-

hyperfractionated radiation and docetaxel

Durable complete responses in heavily

man papilloma virus (HPV)-16 positive

for intermediate risk HPV associated oro-

pretreated patients with metastatic mela-

pharynx cancer. ClinicalTrials.gov.

noma using T-cell transfer immunother-

169. TROG12.01 a randomised trial of weekly

163. A phase II study of lymphodepletion

apy. Clinical Cancer Research: An Official

cetuximab and radiation versus weekly

followed by autologous tumor-infiltrating

Journal of the American Association for Can-

cisplatin and radiation in good prognosis

lymphocytes and high-dose aldesleukin

cer Research 2011; 17: 4550–4557.

locoregionally advanced HPV-associated

162. Phase

II

evaluation

of

for human papillomavirus-associated cancers. ClinicalTrials.gov.

166. Phase II study of de-intensification of radiation and chemotherapy for low-risk HPV-

Copyright © 2015 John Wiley & Sons, Ltd.

patients. ClinicalTrials.gov.

oropharyngeal squamous cell carcinoma. ClinicalTrials.gov.

Rev. Med. Virol. 2015; 25: 54–71. DOI: 10.1002/rmv