Therapeutic vaccination against human papilloma virus induced malignancies

doi:10.1016/j.coi.2010.12.010

Current Opinion in Immunology

Volume 23, Issue 2, April 2011, Pages 252-257

https://doi.org/10.1016/j.coi.2010.12.010 Get rights and content

Human Papilloma Virus (HPV)-induced (pre-)malignancies offer an excellent case for the rational design of immunotherapeutic strategies against cancer. Transformed cells express tumor-specific antigens of viral origin while the spontaneous antitumor response and the immunological make up of HPV-induced tumors do not differ from other immunogenic epithelial tumors. A first clinically active therapeutic HPV vaccine has been developed and clear links were found between the type and kinetics of vaccine-induced T-cell immunity. Here, we will review the mechanisms determining the success and failure of therapeutic vaccines against HPV-induced tumors, with particular emphasis on the immunological setting in which these vaccines need to work. The recent progress in therapeutic HPV vaccination will guide the development of successful vaccines in other diseases.

Introduction

Human Papilloma Virus (HPV) is the most commonly sexually transmitted agent worldwide. Persistent infection with oncogenic HPV types, in particular HPV16 and HPV18, are causally related to the development of anogenital lesions like cervical intra-epithelial neoplasia (CIN) and vulvar intraepithelial neoplasia (VIN) as well as their subsequent progression to invasive squamous cell carcinoma. The HPV genome encodes two oncoproteins, E6 and E7, which are constitutively expressed in high-grade lesions and cancer since they are required for the onset and maintenance of the malignant cellular phenotype. The presence of two defined tumor-specific viral antigens, a group of infected and protected healthy individuals, a clear distinction between patients with premalignant and malignant disease, and the fact that HPV-induced cancer arises more frequently in immune compromised individuals illustrating the role of T cells in this type of cancer, makes HPV-induced cancer an excellent model for the development of immunotherapeutic strategies against cancer. A successful immune mediated regression of a neoplasm requires the induction of a strong tumor-specific Th1/CTL response, the control over several regulatory mechanisms and an immune stimulating microenvironment. Here, we will discuss the recent advances regarding these topics in the field of HPV-induced cancer and integrate them to guide the development of successful immunotherapeutic strategies for cancer, in particular HPV-induced cancer.

Section snippets

Supportive and suppressive microenvironments

The transition from normal epithelium, via low grade and high grade lesions to carcinoma is associated with a loss of locally present IFNγ [1, 2]) and an increase in IL-10 [1, 3]). There is an influx of activated CD4+ and CD8+ T cells [1, 4], which in general do not produce granzyme B [5] and express PD-1 as a sign of exhaustion [6]. Moreover, there is a steady increase in the number of tissue-infiltrating Foxp3+ T cells (regulatory T cells; Tregs), IDO+ cells, and macrophages [1, 7, 8•], all

Local and systemic HPV E6/E7-specific T-cell immunity

Recent studies were dedicated to prospective cohort studies in which the comparison of patient groups with different clinical outcome was central to the analyses of HPV-specific immunity. Two large studies reported that viral persistence corresponds with lack of demonstrable HPV-specific T-cell immunity and suggest that (transient) clearance or regression of lesions is associated with the presence of HPV-specific immunity [18, 19]. Indeed, patients with HPV16-induced high grade cervical lesions

The lessons learned

The studies discussed indicate that most of the different strategies employed by tumors to thwart immune responses are also exploited by HPV-induced (pre-)malignancies. Furthermore, they sustain earlier observations in healthy subjects suggesting that CD4+ and CD8+ type 1 cytokine producing T cells reactive to E6 and E7 have a positive impact on disease outcome but are weak or non-existent and, therefore, need to be resurrected in patients with progressive disease. Moreover, local Tregs and

Yes we can…

Imiquimod has been used to change the microenvironment of HPV-induced VIN3 and this resulted in viral clearance, normalization of immune cell infiltrate, and a complete regression of the lesion in 33% of the patients [30, 31]. Notably, imiquimod-induced VIN3 regression was associated with the presence of circulating HPV-specific Th1 cells [24], suggesting that HPV-specific immunity played a role in the success of this treatment. Moreover, non-responsiveness was associated with the local

Improving current success

The blueprint for highly immunogenic vaccines able to induce the desired immune response thus is there but to become clinically successful, combination with other modalities that target the regulatory mechanisms and the microenvironment are necessary.

Immunoguidance on the road ahead

The current wealth of preclinical and clinical information predicts a future strategy in which therapeutic vaccines, blockers of immunosuppressive mechanisms and conventional therapies are applied jointly to overcome immunological tolerance and promote tumor regression. Clinical efficacy is determined by many different aspects of the interaction of tumors and the immune system, single determinants of which do not necessarily play a role in each and every patient. It will not be trivial to

Conflicts of interest

This study has been conducted by the Leiden University Medical Center (LUMC), which holds a patent on the use of synthetic long peptides as vaccine (US 7.202.034). C.J.M. Melief and S.H. van der Burg are named as inventors on this patent. Note that the LUMC does not share the financial benefit from this patent with its employees.

C.J.M. Melief is partly (75%) employed as of January 20th 2008, by ISA Pharmaceuticals, which exploits this long peptide vaccine patent. C.J.M. Melief has a

References and recommended reading

Papers of particular interest published within the period of review have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The authors of this manuscript are financially supported by several grants from the Dutch Cancer Society (2007-3848; 2009-4400) and the Netherlands Organisation for Scientific Research Zon/Mw (917.56.311; 920.03.425; 40.008.12.98.09012).

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Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3′ end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP’s genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.
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Therefore, there is a great demand for effective treatment of established HPV infection, and therapeutic HPV vaccines are expected to become an effective method to treat HPV. In an attempt to eliminate existing HPV infection or lesions, therapeutic vaccines mainly trigger robust cytotoxic T lymphocyte (CTL) responses against antigens that can be continuously expressed in abnormal cells, thereby enhancing the antitumor effect [8–10]. Two HPV oncogenic proteins, E6 and E7, prevent apoptosis by inhibiting the activation of p53 and pRb, respectively, and further promote cell proliferation, ultimately leading to the development of HPV-related malignant tumors [2,11].
There is a lack of effective treatment methods for advanced cervical, and the therapeutic HPV vaccine is a promising option. The design of an efficient therapeutic vaccine is one of the main challenges. In the current study, we constructed a novel HPV nanovaccine that could effectively inhibit the progression of cervical cancer by combining nanotechnology and photodynamic therapy. This nanovaccine was constructed by linking bovine serum albumin (BSA) with the E7 antigen and then encapsulating the photosensitizer and adjuvant through disulfide bonds to form a highly biocompatible and stable structure. Due to its slow-release properties and targeted delivery to lymph nodes combined with infrared laser irradiation of photosensitizers to produce a photo-oxygen response, this vaccine could effectively induce the maturation of dendritic cells and stimulate T cell effects, thereby enhancing antitumor immunity. This prevention and treatment of tumors was experimentally demonstrated in a TC-1 cervical cancer model in C57BL/6 mice. This strategy can be applied to the design of therapeutic HPV vaccines in the future for clinical use.
Harnessing immunity for therapy in human papillomavirus driven cancers
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In persistent high-risk HPV infection, viral gene expression can trigger some important early changes to immune capabilities which act to protect the lesion from immune attack and subsequently promote its growth and ability for sustained immune escape. This includes immune checkpoint-inhibitor ligand expression (e.g. PD-L1) by tumour or associated immune cells that can block any anti-tumour T-cell effectors. While there are encouraging signs of efficacy for cancer immunotherapies including with immune checkpoint inhibitors, therapeutic vaccines and adoptive cell therapies, overall response and survival rates remain relatively low. HPV oncogene vaccination has shown some useful efficacy in treatment of patients with high-grade lesions but was unable to control later stage cancers. To maximally exploit anti-tumour immune responses, the suppressive factors associated with HPV carcinogenesis must be countered. Importantly, a combination of chemotherapy, reducing immunosuppressive myeloid cells, with therapeutic HPV vaccination significantly improves impact on cancer treatment. Many clinical trials are investigating checkpoint inhibitor treatments in HPV associated cancers but response rates are limited; combination with vaccination is being tested. Further investigation of how chemo- and/or radio-therapy can influence the recovery of effective anti-tumour immunity is warranted. Understanding how to optimally deploy and sequence conventional and immunotherapies is the challenge.
Regulatory T Cells but Not IL-10 Impair Cell-Mediated Immunity in Human Papillomavirus E7+ Hyperplastic Epithelium
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Depletion of CD25+ Tregs during priming of T cells in K14E7tg mice significantly improved the proliferation and effector cytokine secretion by CD8+ T cells but was unable to restore antigen-specific Th1 immunity. Although a causal relationship has not been demonstrated, Th1 immunity during therapeutic vaccination has been a good prognostic predictor for regression of HPV-associated disease in humans (van der Burg and Melief, 2011; Welters et al., 2008). Disease progression has been associated with the presence of Tregs and Th2 responses (Shah et al., 2011; Shang et al., 2015).
High-risk human papillomavirus infection can induce cervical and other intraepithelial neoplasia and invasive cancers. A transgenic mouse expressing keratin 14 promotor-driven HPV16 E7 oncoprotein exhibits epithelial hyperplasia and mimics many features of human papillomavirus–related intraepithelial precancers. We have previously demonstrated that HPV16 E7–mediated epithelial hyperplasia suppresses T helper type 1 responses to intradermally delivered antigen and directs differentiation of CD4⁺ T cells towards a Foxp3⁺ regulatory phenotype (Treg). Here we establish that Foxp3⁺ Treg expansion from a transferred naive T-cell population is driven directly by the hyperplastic skin and is independent of pre-existing immune-modulated lymphocytes. However, depletion of endogenous CD25⁺ Tregs before priming of adoptively transferred T cells significantly improves antigen-specific CD8⁺ T-cell responses but not T helper type 1 responses. Deletion of IL-10 had no effect on Treg expansion, epidermal dendritic cell alteration, and suppression of induced T helper type 1 immunity in HPV16 E7-driven hyperplastic mice. Thus, HPV16 E7–mediated epithelial hyperplasia promotes expansion of peripheral Tregs in response to intradermal immunization that suppress antigen-specific CD8⁺ T-cell responses independently of IL-10, but depletion of these Tregs is not sufficient to restore T helper type 1 immunity.
Human papillomavirus vaccine against cervical cancer: Opportunity and challenge
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Induction of effective cellular immunity to E6, E7, and other viral antigens, may be critical to the efficacy of therapeutic HPV vaccines. The ideal HPV therapeutic vaccines should target these proteins to induce a robust tumor-specific T-cell type 1 and cytotoxic lymphocyte responses where CD4+ T-cells secrete large amounts of cytokines such as IFN-γ and IL2 labeling infected and malignant cells and cytotoxic CD8+ T-cells eliminate infected cells by secreting granzyme B and perforin which lead to cell death [69,70]. Currently, three licensed prophylactic HPV vaccines are available (Table 1): Gardasil®, a quadrivalent HPV (4vHPV) vaccine that targets HPV6, HPV11, HPV16, and HPV18; Cervarix®, a bivalent HPV (2vHPV) vaccine that targets HPV16 and HPV 18; and Gardasil 9®, a nonavalent HPV (9vHPV) vaccine that targets HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58 (Fig. 1).
Cervical cancer is one of the most common cancers threatening women's health, and the persistent infection of high-risk human papillomavirus (HPV) is closely related to the pathogenesis of cervical cancer and many other cancers. The carcinogenesis is a complex process from precancerous lesion to cancer, which provides an excellent window for clinical prevention, diagnosis, and treatment. However, despite the various preventions and treatments such as HPV screening, prophylactic HPV vaccines, surgery, radiotherapy, and chemotherapy, the disease burden remains heavy worldwide. Currently, three types of prophylactic vaccines, quadrivalent HPV vaccine, bivalent HPV vaccine, and a new nonavalent HPV vaccine, are commercially available. Although these vaccines are effective in protecting against 90% of HPV infection, they provide limited benefits to eliminate pre-existing infections. Therefore, new progress has been made in the development of therapeutic vaccines. Therapeutic vaccines differ from prophylactic vaccines in that they aim to stimulate cell-mediated immunity and kill the infected cells rather than neutralizing antibodies. This review aims at systematically covering the progress, current status and future prospects of various vaccines in development for the prevention and treatment of HPV-associated lesions and cancers and laying foundations for the development of the new original vaccine.
Therapeutic vaccines for high-risk HPV-associated diseases
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Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described.

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Therapeutic vaccination against human papilloma virus induced malignancies

Introduction

Section snippets

Supportive and suppressive microenvironments

Local and systemic HPV E6/E7-specific T-cell immunity

The lessons learned

Yes we can…

Improving current success

Immunoguidance on the road ahead

Conflicts of interest

References and recommended reading

Acknowledgements

Mucosal Immunol

Am J Pathol

Gynecol Oncol

Cancer Immunol Immunother

Diminished IFN-gamma and IL-10 and elevated Foxp3 mRNA expression in the cervix are associated with CIN 2 or 3

Int J Cancer

Immunosuppressive cytokine Interleukin-10 (IL-10) is upregulated in high-grade CIN but not associated with high-risk human papillomavirus (HPV) at baseline, outcomes of HR-HPV infections or incident CIN in the LAMS cohort

Virchows Arch

High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer

Cancer Res

Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions

Br J Cancer

Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma

Clin Cancer Res

FOXP3 defines regulatory T cells in human tumor and autoimmune disease

Cancer Res

Indoleamine 2,3-dioxygenase and tumor-induced tolerance

J Clin Invest

HPV16 tumor associated macrophages suppress antitumor T cell responses

Clin Cancer Res

The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2

J Pathol

Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer

Cancer Immunol Immunother

Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysis

BJOG

Local immune response in the microenvironment of CIN2-3 with and without spontaneous regression

Mod Pathol

Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?

Clin Cancer Res

Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma

J Pathol

A prospective study on the natural course of low-grade squamous intraepithelial lesions and the presence of HPV16 E2-,E6- and E7-specific T-cell responses

Int J Cancer

Cell-mediated immune responses to human papillomavirus 16 E6 and E7 antigens as measured by interferon gamma enzyme-linked immunospot in women with cleared or persistent human papillomavirus infection

Int J Gynecol Cancer

Surgery followed by persistence of high-grade squamous intraepithelial lesions is associated with the induction of a dysfunctional HPV16-specific T-cell response

Clin Cancer Res

Naturally occurring systemic immune responses to HPV antigens do not predict regression of CIN2/3

Cancer Immunol Immunother

IFN-gamma produced by human papilloma virus-18 E6-specific CD4+ T cells predicts the clinical outcome after surgery in patients with high-grade cervical lesions

J Immunol

Human papillomavirus 16-specific T cell responses in classic HPV-related vulvar intra-epithelial neoplasia. Determination of strongly immunogenic regions from E6 and E7 proteins

Clin Exp Immunol

Detection of human papillomavirus (HPV) 16-specific CD4+ T-cell immunity in patients with persistent HPV16-induced vulvar intraepithelial neoplasia in relation to clinical impact of imiquimod treatment

Clin Cancer Res

Human papilloma virus specific T cells infiltrating cervical cancer and draining lymph nodes show remarkably frequent use of HLA-DQ and -DP as a restriction element

Int J Cancer

An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer

Cancer Res