Generating HPV specific T helper cells for the treatment of HPV induced malignancies using TCR gene transfer

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.

Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C

“…Poly-ICLC-induced upregulation of HLA class I on infected cells would make them more susceptible to CD8 + T cell recognition and killing. Topical Poly-ICLC might also be combined with targeted immunotherapeutic approaches, such as therapeutic vaccination or adoptive cell transfer of genetically engineered CD8 + and CD4 + T cells with TCR specificity redirected towards either of the viral oncogenes [61, 62]. An increase in local chemokine and interferon production would be expected to enhance the migration of redirected and primed T cells to the site of infection and potentiate their effector functions.…”

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Given the tremendous potential of T-cell engineering exemplified in cancer, one could easily adapt the aforementioned approached to target viruses such as HCV [353], CMV [354], EBV [355,356], HBV [357], and HPV [358,359] or even to treat opportunistic infections [360].…”

Strategies to genetically engineer T cells for cancer immunotherapy

“…Studies have engineered T cells to target antigens, such as CMV [130, 131], EBV [132–134], HIV [135–137], HCV [91–93, 138, 139], HPV [140, 141], and others. No clinical reports have yet been published testing virus-reactive TCR-transduced T cells in humans.…”