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Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid
Ikrame Amara1, Elodie Pramil1, Catherine Senamaud-Beaufort1
1INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
Abstract:
Gene-directed enzyme pro-drug therapy (GDEPT) consists of expressing, in tumor cells, a suicide gene which converts a pro-drug into cytotoxic metabolites, in situ. In a previous work, we demonstrated that the combination of the suicide gene CYP2B6TM-RED (a fusion of a triple mutant of CYP2B6 with NADPH cytochrome P450 reductase) and cyclophosphamide (CPA) constituted a powerful treatment for solid tumors. In this work, we investigated the use of mesenchymal stem cells (MSCs) as cellular vehicles for the delivery of our suicide gene. MSCs were genetically engineered ex-vivo to stably express CYP2B6TM-RED. Ex vivo and in vivo investigations showed that MSCs expressing CYP2B6TM-RED were able 1) to bioactivate CPA and produce local cytotoxic metabolites in tumor sites and 2) to destroy neighboring tumor cells through a bystander effect. Intratumoral injections of CYP2B6TM-RED-MSCs and CPA completely eradicated tumors in 33% of mice without recurrence after 6months. Rechallenge experiments demonstrated an efficient immune response. These data suggest that MSCs expressing CYP2B6TM-RED with CPA could represent a promising treatment for solid tumors to test in future clinical trials.
Insights
Mesenchymal stem cells engineered to carry a suicide gene effectively target solid tumors. This gene therapy approach, combined with cyclophosphamide, eradicated tumors in mice and stimulated an immune response.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Research
Background:
- Gene-directed enzyme pro-drug therapy (GDEPT) uses suicide genes to convert pro-drugs into cancer-killing agents within tumor cells.
- Previous research established CYP2B6TM-RED and cyclophosphamide (CPA) as an effective combination for solid tumor treatment.
Purpose of the Study:
- To evaluate mesenchymal stem cells (MSCs) as delivery vehicles for the CYP2B6TM-RED suicide gene.
- To assess the efficacy of gene-modified MSCs in treating solid tumors in vivo.
Main Methods:
- MSCs were genetically engineered ex vivo to stably express the CYP2B6TM-RED suicide gene.
- In vitro and in vivo studies assessed CPA bioactivation and tumor cell killing by engineered MSCs.
- Tumor eradication and immune response were evaluated in mouse models following intratumoral injection of engineered MSCs and CPA.
Main Results:
- Engineered MSCs successfully bioactivated CPA, generating cytotoxic metabolites at tumor sites.
- MSCs demonstrated a bystander effect, eliminating neighboring tumor cells.
- Intratumoral delivery of CYP2B6TM-RED-MSCs and CPA led to complete tumor eradication in 33% of mice, with no recurrence after six months.
- Rechallenge experiments indicated a robust immune response.
Conclusions:
- MSCs engineered to express CYP2B6TM-RED show potential as a cellular delivery system for GDEPT.
- The combination of CYP2B6TM-RED-MSCs and CPA offers a promising therapeutic strategy for solid tumors.
- Further clinical trials are warranted to explore this approach in human patients.
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