Therapeutic vaccination against human papilloma virus induced malignancies
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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