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Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model
Benjamin Y. Jin, … , Cornelia L. Trimble, Christian S. Hinrichs
Benjamin Y. Jin, … , Cornelia L. Trimble, Christian S. Hinrichs
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99488. https://doi.org/10.1172/jci.insight.99488.
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Research Article Immunology

Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model

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Abstract

T cell receptor (TCR) T cell therapy is a promising cancer treatment modality. However, its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is an attractive therapeutic target that is constitutively expressed by HPV+ cancers but not by healthy tissues. It is unknown if genetically engineered TCR T cells that target E7 can mediate regression of HPV+ cancers. We identified an HPV-16 E7-specific, HLA-A*02:01-restricted TCR from a uterine cervix biopsy from a woman with cervical intraepithelial neoplasia. This TCR demonstrated high functional avidity, with CD8 coreceptor–independent tumor targeting. Human T cells transduced to express the TCR specifically recognized and killed HPV-16+ cervical and oropharyngeal cancer cell lines and mediated regression of established HPV-16+ human cervical cancer tumors in a mouse model. These findings support the therapeutic potential of this approach and established the basis for an E7 TCR gene therapy clinical trial in patients with metastatic HPV+ cancers (NCT02858310).

Authors

Benjamin Y. Jin, Tracy E. Campbell, Lindsey M. Draper, Sanja Stevanović, Bianca Weissbrich, Zhiya Yu, Nicholas P. Restifo, Steven A. Rosenberg, Cornelia L. Trimble, Christian S. Hinrichs

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Figure 1

Identification and optimized expression of a TCR that targets HPV-16 E7.

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Identification and optimized expression of a TCR that targets HPV-16 E7....
(A) IFN-γ production assay testing CILs from 10 patients for recognition of HPV-16 E6 or E7. CILs from each patient were cocultured with autologous dendritic cells loaded with peptide pools spanning the indicated antigen. gp100, also known as melanocyte protein PMEL, is the negative control protein. OKT3 is a positive control of T cells stimulated with plate-bound anti-CD3 antibody. Mel TILs are a negative control of TILs from a melanoma patient. E6 Cntrl and E7 Cntrl are positive controls of T cells genetically engineered to express an E6- or E7-targeting TCR, respectively. The concentration of IFN-γ in supernatants after overnight coculture is displayed. (B) Flow cytometry analysis of 5048 CILs binding to E711–19-HLA-A*02:01 tetramers. E629–38 tetramer is a negative control tetramer. Control T cells are activated, third-party T cells. Dot plots are gated on live lymphocytes. The tetramers were PE labeled. The anti-CD8 antibody was PE-Cy7 labeled. FMO, fluorescence minus one. (C) Flow cytometry analysis of T cells transduced to express the E7 TCR. The schematic for each construct is shown above each dot plot. Orange and brown indicate α and β chain constant regions, respectively. The wild-type interchain disulfide bond is black. The introduced disulfide bond is red. Hydrophobic substitutions to the α chain transmembrane region are green. Variable regions are blue. The α and β chain gene order in the vector insert is indicated to the right of each row. Dot plots are gated on live lymphocytes. Quadrant frequencies are indicated. DS, disulfide; TM, transmembrane; mTRBC, mouse TCR β constant region. The tetramer is APC labeled. The anti-mTRBC antibody is PE labeled. (D) Data from the experiment in C are graphed to display the frequency of transduced T cells (mouse TCR β chain–positive) that did not bind E711–19-HLA-A*02:01 tetramers. Error bars represent the SEM for technical replicates. For C and D, the results are representative of 2 independent experiments.

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