Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer.

Autor: Bandara V; Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia., Niktaras VM; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia., Willett VJ; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia., Chapman H; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia., Lokman NA; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia., Macpherson AM; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia., Napoli S; Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia., Gundsambuu B; Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia., Foeng J; Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide SA Australia., Sadlon TJ; Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia., Coombs J; Carina Biotech, Level 2 Innovation & Collaboration Centre Adelaide SA Australia., McColl SR; Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Sciences The University of Adelaide Adelaide SA Australia.; Carina Biotech, Level 2 Innovation & Collaboration Centre Adelaide SA Australia., Barry SC; Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia., Oehler MK; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.; Department of Gynaecological Oncology Royal Adelaide Hospital Adelaide SA Australia., Ricciardelli C; Reproductive Cancer Research Group, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute University of Adelaide Adelaide SA Australia.
Jazyk: angličtina
Zdroj: Clinical & translational immunology [Clin Transl Immunology] 2024 May 23; Vol. 13 (5), pp. e1512. Date of Electronic Publication: 2024 May 23 (Print Publication: 2024).
DOI: 10.1002/cti2.1512
Abstrakt: Objectives: Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using in vitro and in vivo models.
Methods: We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells in vivo using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.
Results: Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3 + T cells in vitro . However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7-8 weeks.
Conclusion: This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.
Competing Interests: The authors report no conflict of interest.
(© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
Databáze: MEDLINE
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