Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Abstract

Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest virus and adenovirus vector systems in a murine model for cervical cancer

“…Preclinical evaluation of a recombinant replicationdefective Semliki Forest virus (SFV) vector, expressing a fusion protein of HPV type 16 E6 and -E7, has demonstrated the ability of this system to induce strong E6/E7-specific CTL activity in normal 1,3 and immunetolerant E6/E7 transgenic 4 mice and to eradicate pre-established, subcutaneously implanted, HPV-transformed tumours in a murine tumour model. 2 However, despite the apparent potential of this approach, clinical evaluation of an SFV-based therapeutic immunization strategy is hampered by the fact that there is no prior human clinical experience with this vector system which would facilitate regulatory procedures.…”

“…We are developing immunotherapeutic strategies against cervical cancer or premalignant cervical disease using replication-defective recombinant viral vector systems [1][2][3][4][5] or protein-based immunization approaches. 6 Cervical cancer is the second most common type of cancer among women worldwide, and the first malignancy recognized by the World Health Organization to be 100% attributable to infection with a virus, specifically a high-risk type human papillomavirus (HPV).…”

Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

“…Infected cells subsequently die through apoptosis and peptides derived from the recombinant protein may then be presented by professional antigen-presenting cells (APC) in the context of major histocompatibility complex (MHC) class I and class II molecules in a process of cross-presentation. 15,16,[18][19][20][21][22][23][24] The strong booster effect of a second or third immunization with rSFV in a homologous prime-boost protocol is remarkable, as immunization with rSFV has been found to induce robust SFV-specific antibody responses. 15,17 In this study, we have investigated the effect of vector-specific immunity, induced by a priming immunization with rSFV, on transgene expression and CTL activation by a subsequent injection of SFV expressing the E6 and E7 antigens from human papillomavirus (HPV) (SFVeE6,7).…”

Targeted immunotherapy of high‑grade cervical intra‑epithelial neoplasia: Expectations from clinical trials (Review)

“…The other vectors tested, such as the Semliki Forest virus encoding E7, have been shown to induce strong immune responses in mice, but failed to demonstrate any clinical responses, possibly because of the immune tolerance of HPV-infected cells (38,39).…”