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| Home > Publications database > Dual T cell receptor/chimeric antigen receptor engineered NK-92 cells targeting the HPV16 E6 oncoprotein and the tumor-associated antigen L1CAM exhibit enhanced cytotoxicity and specificity against tumor cells. |
| Home > Publications database > Dual T cell receptor/chimeric antigen receptor engineered NK-92 cells targeting the HPV16 E6 oncoprotein and the tumor-associated antigen L1CAM exhibit enhanced cytotoxicity and specificity against tumor cells. |
| Journal Article | DKFZ-2024-00858 |
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2024
Wiley
Bognor Regis [u.a.]
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Please use a persistent id in citations: doi:10.1002/jmv.29630
Abstract: The human papillomavirus type 16 (HPV16) causes a large fraction of genital and oropharyngeal carcinomas. To maintain the transformed state, the tumor cells must continuously synthesize the E6 and E7 viral oncoproteins, which makes them tumor-specific antigens. Indeed, specific T cell responses against them have been well documented and CD8+ T cells engineered to express T cell receptors (TCRs) that recognize epitopes of E6 or E7 have been tested in clinical studies with promising results, yet with limited clinical success. Using CD8+ T cells from peripheral blood of healthy donors, we have identified two novel TCRs reactive to an unexplored E618-26 epitope. These TCRs showed limited standalone cytotoxicity against E618-26-HLA-A*02:01-presenting tumor cells. However, a single-signaling domain chimeric antigen receptor (ssdCAR) targeting L1CAM, a cell adhesion protein frequently overexpressed in HPV16-induced cancer, prompted a synergistic effect that significantly enhanced the cytotoxic capacity of NK-92/CD3/CD8 cells armored with both TCR and ssdCAR when both receptors simultaneously engaged their respective targets, as shown by live microscopy of 2-D and 3-D co-cultures. Thus, virus-specific TCRs from the CD8+ T cell repertoire of healthy donors can be combined with a suitable ssdCAR to enhance the cytotoxic capacity of the effector cells and, indirectly, their specificity.
Keyword(s): Humans (MeSH) ; Oncogene Proteins, Viral: immunology (MeSH) ; Oncogene Proteins, Viral: genetics (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; Repressor Proteins: immunology (MeSH) ; Repressor Proteins: genetics (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Human papillomavirus 16: immunology (MeSH) ; Human papillomavirus 16: genetics (MeSH) ; Cytotoxicity, Immunologic (MeSH) ; Cell Line, Tumor (MeSH) ; CAR ; T cell receptor ; adoptive cell transfer ; cell therapy ; cervical cancer ; chimeric antigen receptor ; human papillomavirus ; immunotherapy ; Oncogene Proteins, Viral ; E6 protein, Human papillomavirus type 16 ; Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell ; Repressor Proteins
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