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Hum Gene Ther ; 29(10): 1202-1212, 2018 10.
Article in English | MEDLINE | ID: mdl-30136612

ABSTRACT

High-risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, and development of HPV-targeted immunotherapy could be used to treat patients with these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult owing to the low frequency of these cell precursors in the peripheral blood. In addition, HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression ex vivo, limiting the efficacy of MHC class I-restricted approaches. Of particular interest is that both CD4 and CD8 T cells can mediate the responses. Given that CD4 T cells play a critical role in coordinating effective antitumor responses, the generation of a T helper response in patients with HPV16-associated malignancies would unleash the ultimate potential of immunotherapy. In this view, T-cell receptor (TCR) gene transfer could be a relevant strategy to generate HPV16-E7-specific and MHC class II-restricted T cells in sufficient numbers. An HPV16-E7/HLA-DRB1*04 TCR has been isolated from a cancer patient with complete response, and retroviral particles encoding this TCR have been produced. The transgenic TCR is highly expressed in transduced T cells, with a functional inducible caspase-9 suicide gene safety cassette. TCR transgenic T cells are HPV16-E770-89 specific and HLA-DRB1*04 restricted, as determined by interferon (IFN)-γ secretion. CD8 and CD4 T cells are equivalently transduced and secrete interleukin-2 and IFN-γ when cultured with appropriate targets. We also demonstrate that TCR transgenic T cells recognize the endogenously processed and presented HPV16-E770-89 peptide. In conclusion, our data indicate that the production of MHC class II-restricted HPV16-E7-specific T cells is feasible through TCR gene transfer and could be used for immunotherapy.


Subject(s)
HLA-DRB1 Chains/immunology , Immunotherapy, Adoptive , Neoplasms/immunology , Neoplasms/therapy , Papillomavirus E7 Proteins/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Chimeric Antigen/metabolism , Animals , Antigen Presentation/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Female , Gene Order , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , HLA-DRB1 Chains/genetics , Humans , Immunophenotyping , Mice , Papillomavirus E7 Proteins/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Chimeric Antigen/genetics , T-Cell Antigen Receptor Specificity , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transduction, Genetic , Transgenes , Xenograft Model Antitumor Assays
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