The Therapeutic Vaccine: Is it Feasible?

In contrast to the prophylactic HPV vaccines that exhibit great promise in reducing the burden of cervical cancer, there is limited progress towards the development of immune therapeutic strategies that would help those women who are already infected with high-risk HPV and do not benefit from the current vaccines. The reason for this drawback is the lack of knowledge about the immune mechanisms that control the growth of HPV-infected or -transformed cells in vivo. It became evident that the preclinical models in rodents provide only limited information about the performance of a candidate vaccine in humans. In particular, the immune correlate for a clinical response remains to be determined. On the other hand, HPV-related malignancies provide an excellent model for cancer immune therapies in general. There is hope that the continuous efforts of academic research combined with corporate involvement will finally present an efficient product.

Introduction

High-risk papillomaviruses are able to initiate persistent infections. From the perspective of a virus with low replication capacity (like HPV16), this is a reasonable strategy to ensure spread within a population and thus to survive. On the other hand, the ability to persist within a cell in the absence of virus replication that typically is associated with cell death is the prerequisite for the capacity of a given virus to transform a cell into uncontrolled growth and, as a consequence, induce cancer.

Papillomaviruses have developed different strategies to escape the immune control and thus establish a persistent infection. Typically the immune system does not recognize papillomaviruses because they remain restricted to the affected epithelium, i.e., there is no viremic spread to other organs. There is also low expression of viral proteins within the basal and first suprabasal layer in the absence of cell death, hence without induction of danger signals that would alert the innate immune system. Virus production occurs in the superficial, differentiated cells with limited or no interaction with the immune system.

In addition to this low-profile strategy, human papillomaviruses are also able to actively suppress the antiviral effect of the immune system, most effectively already at the level of the innate response. This suggestion stems from the results of a clinical study that demonstrated the inverse correlation between the expression of the E7 gene within a cervical lesion and its response to interferon (1). This observation was corroborated by experimental studies that demonstrated the interference of the E6 and E7 proteins of HPV 16 and 18 with the expression of TLR 9 (2) and type I interferons as well as with downstream events within the interferon-induced pathways (for review see Reference 3). Another immune-inhibitory effect of the viral oncoproteins is the inhibition of migration of APCs from the epithelium as required to exert their function within the lymph nodes 4, 5 and the strong reduction of the amount of surface MHC I molecules that are necessary for specific recognition by cytotoxic T cells (6).

Despite the immunosuppressive capacities and the hiding of the virus, the immune system nevertheless does participate in the control of HPV infections. There is an increased risk of HPV infections and associated lesions in immunosuppressed patients. For example, HIV-positive women with reduced CD4+ cell count are up to 8-fold more likely to develop a persistent genital HPV infection and a cervical dysplasia (7). Also, in some of the HPV-infected individuals, virus-specific T helper and/or cytotoxic T cells can be detected that are typically directed against the early proteins E2, E6 and E7 (for summary see References 8, 9, 10) and are often associated with the regression of the lesion. In regressing warts, infiltrating macrophages, NK cells and/or CD4+ lymphocytes have been detected 11, 12. Successful treatment with interferon of HPV-induced anal lesions goes along with infiltration by T-helper 1 cells that are characteristic for a delayed-type hypersensitivity reaction. When treatment fails, the patients showed a depletion of Langerhans' cells, reduction of MHC II expression in keratinocytes and of the cytokines IL-1a, -1b and GM-CSF (13). Similar observations have been made in patients after treatment with an immune modulator (imiquimod) that stimulates the innate immune system via TLR 7 14, 15. A humoral immune response against early HPV proteins can only occasionally be detected during the natural course of an infection and occurs typically only in patients with HPV-related malignant diseases 16, 17, 18. Measurable antibodies directed against the viral structural proteins occur in about half of the infected subjects and are considered a marker for virus persistence.