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Review

Human papillomavirus-specific immune therapy: failure and hope

Karen Nieto1, Lutz Gissmann1,2,*, Lysann Schädlich1

1Infection and Cancer Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Department of Botany and Microbiology, King Saud University, Riyadh, Saudi Arabia

*Corresponding author e-mail: l.gissmann@dkfz.de

Citation: Antiviral Therapy 2010; 15:951-957
doi: 10.3851/IMP1665

Date accepted: 15 April 2010
Date published online: 28 September 2010

Copyright (c) 2010 International Medical Press, all rights reserved.

Abstract

Recently, two prophylactic vaccines against the most significant oncogenic human papillomaviruses (HPV; 16 and 18) became available that efficiently protect against persistent HPV infection and cancer precursors. However, clinical trials performed with these vaccines did not provide evidence that they would influence the natural history of prevalent HPV infections, that is, their eventual malignant progression. Because, even under the optimistic assumption of high vaccine coverage, a significant reduction of cancer incidence can only be expected after two decades, there is a need for immune therapeutic strategies to be offered to persistently infected individuals who do not benefit from the prophylactic vaccines. Here, we describe the reasons for failure of most of the published approaches to HPV-specific therapies, highlight promising developments and present our view for future developments.

Transformation by high-risk HPV is the consequence of persistent infections

Human papillomaviruses (HPVs), which exist as members of a large family, can cause a variety of epithelial diseases at the skin or mucosae. The clinical appearance ranges from typical exophytic warts to inconspicuous flat intraepithelial lesions that are often located in the genital tract, called cervical, vulval, vaginal, penile or perianal intraepithelial neoplasia. Papillomaviruses are adapted to the differentiation programme of the epithelia; production of virus progeny occurs in the superficial terminally differentiated cells from which the particles are released into the environment. HPV types that are associated with exophytic warts or intraepithelial lesions replicate with different efficiencies; cutaneous HPV types that induce hand or foot warts produce relatively large quantities of HPV particles, whereas typically, only minute amounts of virus progeny are made following infection with the mucosal viruses [1]. This difference might reflect the usually tight skin-to-skin contact that is involved in transmission of genital HPV types, whereas infection by cutaneous types appears to occur easily, via contaminated objects also [2]. However, this very direct mode of transmission might not be sufficient to assure survival of HPV types within a population; therefore, they have developed a strategy of persistence in the epithelium, which assures maintenance for a prolonged time, thus providing repeated chances for successful transmission. Persistence is known in both cutaneous and mucosal types, although the mechanisms might be quite different. It is unclear whether persistence of the virus is a consequence of reinfection of the same area or is caused by maintenance of viral DNA in basal epithelial cells; possibly in stem cells.

It is well-established that persistent infection is a prerequisite for the eventual and rather slow development of malignant anogenital tumours. This has been best established for cancer of the uterine cervix, which is associated with different so-called high-risk HPV types, most importantly HPV 16, 18, 31, 33, 35 and 58, which are all members of the species A7 and A9 of the genus Alpha papillomaviruses [3]. Precursor lesions of cervical cancer arise as a consequence of such persistent infection within a few years. The chain of events is a matter of debate – does infection first lead to low-grade lesions with virus production from which persistence might develop or can infection lead directly to persistence? What determines the switch between transient, that is productive, and persistent infections? It is probable that immune functions, which are not fully understood, enable the clearance of the infection or at least the reduction of virus load to an undetectable level. Several lines of evidence are consistent with this notion, for example, the increased risk of persistence of multiple HPV types in immunosuppressed individuals [4], the often observed higher prevalence of infection in women >55 years of age [5] and the increased risk, with age, of developing persistence following primary infection [6]. One can assume that the properties of high-risk papillomaviruses (studied mostly in HPV 16 but probably applicable to other cancer-related HPV types) that allow them to passively and actively avoid immune surveillance [7] are the keys to establishing and maintaining the state of persistence.

We have accumulated substantial knowledge regarding the mechanism of malignant transformation, mostly based upon the interaction of the non-structural (‘early’) gene products E6 and E7 with a variety of cellular proteins that control cell cycle, apoptosis, genomic stability, cell adhesion and cell polarity [8]. As a result of work with organotypic keratinocyte cultures and other sophisticated models [9], we are also learning more about the replicative cycle of papillomaviruses, including the initial steps of infection [10,11]. In notable contrast to this growing awareness, the term ‘persistent infection’ is purely operational and we have no knowledge of the underlying molecular mechanism. Persistence is defined as repeated detection of the same HPV type from consecutive clinical specimens (for example, a cervical swab) of an individual. It should be noted that this ‘infection’ is determined by measuring viral DNA via a highly sensitive method that cannot discriminate between virus or infected cells deposited from another source and virus produced within an individual. It is possible that detection of viral RNA can differentiate between incoming and replicated virus. In addition, data from such analyses will help to define the state of persistent infection more precisely and give some hints as to the underlying mechanisms.

Why have previous attempts at HPV-specific immune therapy largely failed?

Progression from a productive HPV infection towards a high-grade lesion and cancer is characterized by the change in the typically well-controlled pattern of viral gene expression [10]. During this process, the late genes are shut down, particle production in the superficial cells ceases, and the compartment of E6/E7-positive cells extends throughout the whole epithelium. Natural history studies have revealed that healthy individuals with evidence of previous exposure to HPV 16 have, in comparison with patients with HPV-associated neoplasia, relatively strong T-cell responses against these early viral proteins [12,13]. Based on these findings, it was a reasonable assumption that E6 and E7 are suitable targets for an HPV-specific immune response and, indeed, most of the vaccines used for HPV-specific immune therapy are directed against the E6/E7 proteins.

The initial clinical trials were conducted with late-stage cancer patients to evaluate the safety of the respective vaccine [14]. Certainly, none of the investigators who initiated these early studies assumed that cervical cancer could be treated with a syringe. Because of the immunosuppressive milieu generated by established tumours [15], it appears that (similar to cancer immunotherapy in general) in cases of advanced disease, an immunological antitumour effect will, if at all, only be successful along with standard therapy [16]. Cervical cancer proved to contain even higher numbers of infiltrating FOXP3+ regulatory T-cells (Treg) [17] as compared with colonic or bronchial carcinoma or malignant melanoma [18]. Obviously, Tregs suppress an efficient antitumour response despite the presence of HPV E6- or E7-specific CD4+ and CD8+ T-lymphocytes within the tumour and the draining lymph nodes [19].

Later attempts took advantage of the unique situation in HPV-related carcinogenesis, that is, the existence of well-defined precursors to cervical, anal or vulval cancer. Several clinical studies have been completed, investigating treatment of patients with such high-grade intraepithelial lesions (cervical intraepithelial neoplasia [CIN], anal intraepithelial neoplasia [AIN] and vulval intraepithelial neoplasia [VIN]; for a review see [20]). Although the effects were, in general, quite promising, these trials were not powered to detect small effects in the vaccine versus the placebo groups. Typically, there was no follow-up study with the same strategy, most probably because these trials were investigator-initiated or sponsored by small biotech companies. Large pharmaceutical corporations that could have ensured continuation of the individual programme were not involved.

Another weakness of most of the therapeutic trials was the lack of clear-cut immune correlates that differentiated clinical responders from non-responders. The reason for the absence of detectable immune responses in clinical responders might be the use of assays with insufficient sensitivity. Monitoring of immune responses was not carried out by the technically demanding analysis of measuring the local immune response within or around the tumour that is impracticable under conditions of a clinical trial. Instead, circulating lymphocytes were determined, which might not reach a concentration that would permit their detection. The issue of sensitivity is supported by unpublished data (A Kaufmann and LG) on local T-cell responses induced by intradermal injection of HPV 16 E7-derived peptides into high-grade CIN patients who had participated in a clinical trial with chimeric virus-like particles (VLPs) consisting of an HPV 16 L1/E7 fusion protein [21]. Although, peripheral blood lymphocytes specific for L1 or E7 did not correlate with clinical outcome, there was a perfect match in the case of the local E7-specific skin reaction (A Kaufmann and LG, unpublished observations). A different explanation needs to be suggested for the opposite situation, that is, the presence of a T-cell response without a clinical effect. It is possible that peripheral blood mononuclear cells and lymphocytes homing to the tumour tissue might be directed against different viral epitopes, as has been reported in patients with therapy-resistant genital warts [22].

There is light at the end of the tunnel

Persistence in the development of a vaccine candidate becomes realistic

Encouraging results in animal studies have been obtained with viral vectors (for example, Semliki Forest virus, adenovirus, adeno-associated virus [2325]; for a review see [20]); however, with the exception of recombinant vaccinia [20], the stage of clinical evaluation has not yet been reached. In a follow-up of an earlier development, a modified vaccinia strain with clinically established safety (Modified Vaccinia Ankara [MVA] virus) has been generated as a vector for treatment of HPV-related neoplasia. It contains the HPV 16 genes E6 and E7 (modified in the p53 or pRB binding sites of the respective proteins) plus the interleukin-2 gene [26]. In a Phase II trial, 21 patients with CIN 2/3 received three subcutaneous injections of 5×107 plaque-forming units. After 6 months, 10 out of 18 women presented with normal colposcopy, 9 out of 18 were without histological evidence of CIN or HPV 16 E6/E7 RNA. At 12 months follow-up, all six available women were CIN- and HPV-negative (Roche and Transgene, unpublished data). This result would not, in itself, be notable, in particular because no placebo control arm was included and no immunological data has been reported; also, the available information is based only on company press releases. The most encouraging aspect of this project is the partnership announced in 2007 between a large pharmaceutical firm (Roche) and a biotech company (Transgene) that has so far been driving this approach. Hopefully, this combined effort will ensure continuation in development, even in the absence of immediate success.

A recombinant vector deserves attention

The development of a recombinant vector that was originally designed to induce a non-immunological direct antitumour effect, is also based on MVA technology. In an attempt to exploit the ability of the E2 protein to inhibit the expression of the E6 and E7 oncoproteins of a non-homologous papillomavirus [27], Valdez Graham et al. [28] inserted the E2 gene of the bovine papillomavirus type-1 3′ to the p 7.5 promoter of MVA. Although a successful preclinical study seemed to suggest an immunological component [29], intralesional application was chosen in three clinical Phase I/II trials. A total of 100 patients with CIN or flat condylomas (males) received 4–6 injections of 106 or 107 plaque-forming units of E2 recombinant MVA (rMVA). The controls were treated by standard protocols. No severe adverse effects related to the rMVA were observed. At 3–4 weeks after the last injection, >90% of the patients showed complete or partial clinical response and there was a significant reduction of the virus load in the patient that received the recombinant vector [23,30,31]. Although no data from a longer follow-up was presented and the immune responses observed in the patients (antibodies against the recombinant virus and cytotoxic T-lymphocytes against autologous tumour cells) were not well-defined, this approach deserves further evaluation.

Long peptides are superior

Among the less successful strategies for HPV immune therapy was the use of short (8–11 amino acids) synthetic peptides [32,33]. As demonstrated in a mouse study, such peptides tolerize cytotoxic T-lymphocyte activity and might instead enhance tumour growth [34]. Long (25–35 amino acids) synthetic peptides have proven to be effective in the eradication of established HPV-positive tumours in an animal model [35]. This difference has been assigned to the ability of short peptides to bind exogenously to major histo-compatibility complex class I molecules and also to non-professional antigen presenting cells (for example, B-cells), leading to a temporary T-cell response that is followed by deletion of these CD8+ T-cells [36,37]. By contrast, long peptides need to be processed in order to be presented to T-cells. This is carried out by professional antigen-presenting cells under conditions of immune stimulation within the lymph node [38]. These features were exploited in clinical trials with long peptides (emulsified in incomplete Freund’s adjuvant) that cover the entire HPV 16 E6 and E7 proteins in an overlapping fashion. After demonstration of safety and induction of CD4+ and CD8+ T-cell immunogenicity in a Phase I clinical trial [39,40], 20 women with histologically confirmed HPV-16-positive VIN grade 3 were enrolled in a Phase II study [41]. They received three or four subcutaneous injections of this vaccine (0.3 mg per peptide) at 3-week intervals. The investigators noted a complete response in 9 out of 19 and a partial response in 6 out of 19 patients 12 months after the last vaccination. Considering the extremely low rate of spontaneous remission of VIN 3, this is a very promising result. Another interesting aspect of this study is the fact that the induced HPV-specific CD4+ and CD8+ T-cell responses correlate with the clinical response.

Similarly encouraging data on immune therapeutic effects against VIN 3 have been published [42]. In this study, 19 patients received three doses of an HPV 16 L2E6E7 fusion protein (TA-CIN) [43] following treatment with the immune modifier imiquimod [44]. At 1 year of follow-up, complete remission was observed in 12 out of 19 women. A total of 5 out of 19 patients had cleared HPV DNA. There was an increased infiltration of CD4+ and CD8+ T-lymphocytes in responders. By contrast, non-responders presented with an increased number of Tregs.

What might be future developments?

Targeting persistent infections

As previously mentioned, there are promising developments towards immune therapy of precursor lesions in HPV-related cancer; however, is it possible that, altogether, targeting such premalignant diseases is still too ambitious? Possibly similar mechanisms of immune escape and immune suppression, as seen in cancer, are already active in such premalignant lesions [18,45,46]. If so, one might consider targeting persistent infections before they become clinically apparent. What has been called a ‘paradigm shift’ in vaccination of cancer patients [16] is a quite logical step in HPV-related cervical cancer. Because persistent infection, even if poorly defined, is the prerequisite of the development of malignancy, treating this early condition with post-exposure prophylaxis [47] might be more successful than therapy at more advanced stages. Several well-defined cohorts of women with persistent infections do exist [4850], and the design and execution of clinical trials aiming to analyse efficacy (that is, clearing of HPV DNA) should be straightforward.

Choice of antigen

To date, most of the strategies that have been used target the E6 and/or E7 proteins; however, there might be other options. As mentioned earlier, in a series of clinical trials, recombinant vaccinia expressing the E2 (E2 rMVA) gene were investigated, and considerable success was achieved [23,30,31]. There might be a caveat with regard to this approach because, typically, the E2 gene is either mutated or functionally inactivated in cervical cancer cells [51,52]; thus, ensuring the constitutive expression of the E6 and E7 oncogenes. Therefore, inducing E2-specific immunity might select for E2-negative cells with an increased risk of progression. E1 is another protein that is expressed early during papillomavirus infection and, along with E2, facilitates HPV DNA replication [53]; therefore, it might be considered another target for therapy of virus-producing low-grade lesions. No experimental data are available regarding T-cell epitopes in E1, but, given the size of this protein (approximately 70 kD), it is very likely that they do exist. Encouraged by the data with the E2 rMVA, studying the other protein that is involved in HPV DNA replication might be worthwhile.

Optimizing the immunization scheme

There is mounting evidence that a heterologous prime-boosting immunization scheme (that is, the same antigen being presented by different delivery systems) is superior to a repeated application of the same vaccine. For example, a frequently used protocol yielding promising results towards protection against tuberculosis or malaria is priming by DNA, followed by a boost with protein or a recombinant vector [54]. Indeed, a heterologous scheme has already been applied to HPV-specific immune therapy. One published clinical trial employed priming by an HPV 16 L2E6E7 fusion protein and boosting by E6/E7 recombinant vaccinia. The authors noted no advantages over a vector-only vaccination scheme [55]; however, we feel that such sophisticated schemes of immunization deserve further attention because previous studies have shown that subtle differences in the protocol can be crucial and that the optimal conditions are unpredictable [56]. Our own preclinical data on an HPV 16 vaccine with combined prophylactic and therapeutic properties in different adeno-associated virus-based vectors clearly highlight the importance of the correct vaccination protocol [57]. An, as yet, unpublished modification superior to the standard vaccination protocol that has been worked out in a mouse model encompasses intramuscular priming followed by intravaginal application of immune stimulatory molecules (for example, CpG oligonucleotides; D Nardelli-Haefliger, University of Lausanne, personal communication). This approach deserves further investigation because it induces the attraction of effector cells to the site of action.

The reported effects of DNA vaccination cannot be easily applied to HPV-specific T-cell responses because the major targets are the oncoproteins E6 and E7, and it is not feasible to inject a gene with transforming properties into human beings. To take advantage of the power of DNA immunization (especially in combination with a heterologous boost) we developed the concept of shuffled HPV oncoproteins. In these vectors, we have rearranged the sequences in such a way that no transforming activity is detectable; however, all putative T-cell epitopes have been maintained [58,59].

Therapeutic effect of prophylactic vaccines

In studies on the natural history of HPV infections there was no evidence that an L1-specific T-cell response (unlike the response to early proteins) can influence the development of cervical neoplasia [60]. The clinical trials with the two available HPV vaccines that consist of L1 VLPs did not show evidence of a therapeutic effect. Independent of being randomized into the placebo or vaccine arm, women that were HPV-positive at enrolment had the same risk of maintaining the infection and of developing a lesion [6163]. Conversely, a therapeutic effect on the development of papillomas was reported in rabbits that had been immunized with L1 VLPs of the cottontail rabbit papillomavirus. Similarly, VLPs of HPV 6 were shown to induce a prolonged disease-free interval in patients with persistent HPV-6-positive genital warts when compared with historical controls [64]. These effects might be the consequence of different modes of persistence of HPV in keratinized skin and at the cervical mucosa; whereas, it is generally accepted that the DNA of high-risk HPV types persists within the basal cells, it is feasible that low-risk types maintain themselves by reinfection of cells in the same area. Although an effect of an L1-specific T-cell response cannot be excluded, one can assume that neutralizing antibodies might interfere with this reinfection, thus, inducing a quasi-therapeutic effect. Direct evidence in favour of this hypothesis comes from patients with recurrent laryngeal papillomatosis who received the tetravalent vaccine containing VLPs of HPV 6 and HPV 11. These patients had almost no measurable antibodies prior to immunization, but developed high titres of L1-specific antibodies thereafter. This response was accompanied by prolonged disease-free intervals [65]. These anecdotal reports clearly warrant further investigation in well-controlled clinical studies.

Disclosure statement

The authors declare no competing interests.

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