Abstract
BackgroundInfection with high risk Human Papilloma Virus (HPV) is associated with cancer of the cervix, vagina, penis, vulva, anus and some cases of head and neck carcinomas. The HPV derived oncoproteins E6 and E7 are constitutively expressed in tumor cells and therefore potential targets for T cell mediated adoptive immunotherapy. Effective immunotherapy is dependent on the presence of both CD4+ and CD8+ T cells. However, low precursor frequencies of HPV16 specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer purposes. An alternative to generate HPV specific CD4+ and CD8+ T cells is TCR gene transfer.MethodsHPV specific CD4+ T cells were generated using either a MHC class I or MHC class II restricted TCR (from clones A9 and 24.101 respectively) directed against HPV16 antigens. Functional analysis was performed by interferon-γ secretion, proliferation and cytokine production assays.ResultsIntroduction of HPV16 specific TCRs into blood derived CD4+ recipient T cells resulted in recognition of the relevant HPV16 epitope as determined by IFN-γ secretion. Importantly, we also show recognition of the endogenously processed and HLA-DP1 presented HPV16E6 epitope by 24.101 TCR transgenic CD4+ T cells and recognition of the HLA-A2 presented HPV16E7 epitope by A9 TCR transgenic CD4+ T cells.ConclusionOur data indicate that TCR transfer is feasible as an alternative strategy to generate human HPV16 specific CD4+ T helper cells for the treatment of patients suffering from cervical cancer and other HPV16 induced malignancies.
Highlights
Infection with high risk Human Papilloma Virus (HPV) is associated with cancer of the cervix, vagina, penis, vulva, anus and some cases of head and neck carcinomas
E6 and E7, responsible for both onset and maintenance of malignant transformation, are constitutively expressed in HPV induced cancers and represent non-self tumorassociated antigens. As such the HPV antigens E6 and E7 are high on the priority-ranked list of cancer vaccine target antigens[7] In previously described clinical trials applying adoptive transfer of melanoma specific CD8+ T cells, no objective clinical responses were found in melanoma patients while melanoma specific CD8+ T cells were highly reactive against tumor cells in vitro[8]
In this paper we show that T helper function, as measured by specific cytokine production, against HPV16 antigens can be obtained after transfer of MHC class I or MHC class II restricted HPV specific T cell receptor (TCR) into CD4 + T cells
Summary
Infection with high risk Human Papilloma Virus (HPV) is associated with cancer of the cervix, vagina, penis, vulva, anus and some cases of head and neck carcinomas. Adoptive transfer of HPV specific T cells could be an attractive strategy to treat patients suffering from HPV induced malignancies. E6 and E7, responsible for both onset and maintenance of malignant transformation, are constitutively expressed in HPV induced cancers and represent non-self tumorassociated antigens. As such the HPV antigens E6 and E7 are high on the priority-ranked list of cancer vaccine target antigens[7] In previously described clinical trials applying adoptive transfer of melanoma specific CD8+ T cells, no objective clinical responses were found in melanoma patients while melanoma specific CD8+ T cells were highly reactive against tumor cells in vitro[8]. CTL responses against HPV antigens in women with natural HPV infections are difficult to detect indicating that the precursor frequencies of HPV specific CTLs are very low, making it difficult to isolate these HPV specific T cells[11,12]
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