%0 Journal Article
%A Quiros-Fernandez, Isaac
%A Libório-Ramos, Sofia
%A Leifert, Lena
%A Schönfelder, Bruno
%A Vlodavsky, Israel
%A Cid-Arregui, Angel
%T 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.
%J Journal of medical virology
%V 96
%N 5
%@ 0146-6615
%C Bognor Regis [u.a.]
%I Wiley
%M DKFZ-2024-00858
%P e29630
%D 2024
%Z #EA:D122#LA:D122#
%X 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.
%K Humans
%K Oncogene Proteins, Viral: immunology
%K Oncogene Proteins, Viral: genetics
%K Receptors, Chimeric Antigen: immunology
%K Receptors, Chimeric Antigen: genetics
%K Receptors, Antigen, T-Cell: immunology
%K Receptors, Antigen, T-Cell: genetics
%K Repressor Proteins: immunology
%K Repressor Proteins: genetics
%K CD8-Positive T-Lymphocytes: immunology
%K Killer Cells, Natural: immunology
%K Human papillomavirus 16: immunology
%K Human papillomavirus 16: genetics
%K Cytotoxicity, Immunologic
%K Cell Line, Tumor
%K CAR (Other)
%K T cell receptor (Other)
%K adoptive cell transfer (Other)
%K cell therapy (Other)
%K cervical cancer (Other)
%K chimeric antigen receptor (Other)
%K human papillomavirus (Other)
%K immunotherapy (Other)
%K Oncogene Proteins, Viral (NLM Chemicals)
%K E6 protein, Human papillomavirus type 16 (NLM Chemicals)
%K Receptors, Chimeric Antigen (NLM Chemicals)
%K Receptors, Antigen, T-Cell (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38659368
%R 10.1002/jmv.29630
%U https://inrepo02.dkfz.de/record/289779