Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for
Veronika Bandara1, Victoria M Niktaras2, Vasiliki J Willett2
1Molecular Immunology, Robinson Research Institute University of Adelaide Adelaide SA Australia.
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.
Insights
Chimeric antigen receptor T-cell therapy targeting the non-functional P2X7 receptor shows promise for ovarian cancer. nfP2X7-CAR-T cells effectively reduced ovarian cancer cell survival and tumor burden in preclinical models.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- The non-functional P2X7 (nfP2X7) receptor is expressed on ovarian cancer cells but not normal cells.
- This makes nfP2X7 a potential target for chimeric antigen receptor (CAR)-T-cell immunotherapy in ovarian cancer.
Purpose of the Study:
- To assess the efficacy of nfP2X7-CAR-T cells against ovarian cancer using in vitro and in vivo models.
- To evaluate the cytotoxic effects of nfP2X7-CAR-T cells on various ovarian cancer cell lines, primary patient cells, and in a mouse xenograft model.
Main Methods:
- In vitro studies utilized ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9), and patient-derived primary serous ovarian cancer cells.
- 3D spheroid and patient-derived tissue explant assays were employed, alongside an in vivo OVCAR-3 xenograft model in NSG mice.
Main Results:
- nfP2X7-CAR-T cells demonstrated significant cytotoxicity against OVCAR3, OVCAR5, and primary ovarian cancer cells in vitro.
- Treatment increased apoptosis in patient-derived explants and significantly reduced tumor burden in the OVCAR-3 xenograft mouse model.
- SKOV3 cells and normal peritoneal cells showed limited response due to low nfP2X7 expression.
Conclusions:
- nfP2X7-CAR-T cells exhibit potent anti-tumor activity against ovarian cancer.
- These findings highlight the potential of nfP2X7-CAR-T cells as a novel immunotherapy for ovarian cancer.
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