TY  - JOUR
AU  - Quiros-Fernandez, Isaac
AU  - Libório-Ramos, Sofia
AU  - Leifert, Lena
AU  - Schönfelder, Bruno
AU  - Vlodavsky, Israel
AU  - Cid-Arregui, Angel
TI  - 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.
JO  - Journal of medical virology
VL  - 96
IS  - 5
SN  - 0146-6615
CY  - Bognor Regis [u.a.]
PB  - Wiley
M1  - DKFZ-2024-00858
SP  - e29630
PY  - 2024
N1  - #EA:D122#LA:D122#
AB  - 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.
KW  - Humans
KW  - Oncogene Proteins, Viral: immunology
KW  - Oncogene Proteins, Viral: genetics
KW  - Receptors, Chimeric Antigen: immunology
KW  - Receptors, Chimeric Antigen: genetics
KW  - Receptors, Antigen, T-Cell: immunology
KW  - Receptors, Antigen, T-Cell: genetics
KW  - Repressor Proteins: immunology
KW  - Repressor Proteins: genetics
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Killer Cells, Natural: immunology
KW  - Human papillomavirus 16: immunology
KW  - Human papillomavirus 16: genetics
KW  - Cytotoxicity, Immunologic
KW  - Cell Line, Tumor
KW  - CAR (Other)
KW  - T cell receptor (Other)
KW  - adoptive cell transfer (Other)
KW  - cell therapy (Other)
KW  - cervical cancer (Other)
KW  - chimeric antigen receptor (Other)
KW  - human papillomavirus (Other)
KW  - immunotherapy (Other)
KW  - Oncogene Proteins, Viral (NLM Chemicals)
KW  - E6 protein, Human papillomavirus type 16 (NLM Chemicals)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
KW  - Receptors, Antigen, T-Cell (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38659368
DO  - DOI:10.1002/jmv.29630
UR  - https://inrepo02.dkfz.de/record/289779
ER  -