Therapeutic vaccination against human papilloma virus induced malignancies

https://doi.org/10.1016/j.coi.2010.12.010Get 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).

References (54)

  • D.H. Munn et al.

    Indoleamine 2,3-dioxygenase and tumor-induced tolerance

    J Clin Invest

    (2007)
  • A.P. Lepique et al.

    HPV16 tumor associated macrophages suppress antitumor T cell responses

    Clin Cancer Res

    (2009)
  • H.J. Zijlmans et al.

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

    J Pathol

    (2006)
  • A. Battaglia et al.

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

    Cancer Immunol Immunother

    (2009)
  • Y.L. Woo et al.

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

    BJOG

    (2008)
  • I.T. Ovestad et al.

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

    Mod Pathol

    (2010)
  • E.S. Jordanova et al.

    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

    (2008)
  • J.N. Kloth et al.

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

    J Pathol

    (2008)
  • Y.L. Woo et al.

    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

    (2010)
  • S. Farhat et al.

    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

    (2009)
  • P.J. de Vos van Steenwijk et al.

    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

    (2008)
  • C.L. Trimble et al.

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

    Cancer Immunol Immunother

    (2010)
  • S. Seresini et al.

    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

    (2007)
  • I. Bourgault Villada et al.

    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

    (2010)
  • M.I. van Poelgeest et al.

    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

    (2005)
  • S.J. Piersma et al.

    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

    (2008)
  • P.J. de Vos van Steenwijk et al.

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

    Cancer Res

    (2010)
  • Cited by (100)

    View all citing articles on Scopus
    View full text