CardioVascular and Interventional Radiology

, Volume 41, Issue 1, pp 153–162 | Cite as

Hepatic Intra-arterial Delivery of a “Trojan-horses” Gene Therapy: A Pilot Study on Rabbit VX2 Hepatic Tumor Model

  • Olivier Pellerin
  • Ikram Amara
  • Marc Sapoval
  • Tchao Méachi
  • Carole Déan
  • Philippe Beaune
  • Isabelle de Waziers
Laboratory Investigation

Abstract

Purpose

Gene-directed enzyme prodrug therapy (GDEPT) is a “Trojan-horses” suicide gene therapy that consists of tumor-targeted gene delivery (vectorized by mesenchymal stem cells MSCs) encoding an enzyme that converts a harmless prodrug into cytotoxic metabolites in situ. Then, cytotoxic metabolites passively diffuse in the neighboring tumor cells and kill them (bystander effect). The goal of our study was to assess the feasibility and efficacy of intra-arterial administration of MSCs transduced with an optimized gene (MSC-CYP2B6TM-RED) followed by intravenous administration of cyclophosphamide (CPA) into the VX2 rabbit liver tumor.

Materials and Methods

Nine rabbits with a VX2 liver tumor were randomly assigned into three groups: Control group A (one rabbit) free of any treatment; Control group B (two rabbits) receiving intravenous injection of cyclophosphamide at day 3 and CPA at day 14; and Group C (six rabbits) receiving the GDEPT treatment, consisting of successive intra-arterial injection of transduced-MSCs at days 0 (n = 6) and 11 (n = 3), followed by injection of CPA at days 3 (n = 6) and 14 (n = 3). The tumor response was assessed by ultrasound scan every 7 days and histopathological analysis at sacrifice (D25).

Results

There was a significant difference in the tumor volume between control groups (A + B) and group C at D7: 38/19 cm3 (p = 0.024); D11: 51/20 cm3 (p = 0.024), and D25: 121/37 cm3 (p = 0.048). Tumor necrosis was significantly greater and metastatic spread was lower for rabbits who received GDEPT (78% of total tumor surface) than for control animals (A + B) (22% of total tumor surface (p = 0.006).

Conclusion

Intra-arterial delivery of transduced-MSCs is feasible and, after CPA injection, resulted in 78% tumor necrosis (p = 0.006) and less metastasis in a VX2 liver tumor model.

Keywords

Gene-directed enzyme prodrug therapy Intra-arterial delivery Liver cancer Rabbit VX2 

Notes

Acknowledgements

This work has been selected by the CIRSE 2017 Scientific Programme Committee and the CVIR Editorial Board, and cordially invited to send a complete manuscript for publication in the official journal of CIRSE, the CardioVascular and Interventional Radiology (CVIR). This work was supported by SATT Ile de France and the Ligue Nationale contre le Cancer, comités d’Ile de France. Ikrame Amara was a graduate student funded by the Cancéropole Ile-de-France. Baxter freely provided Cyclophosphamid. We acknowledge Julien Namur, Florentina Pascale from Archimmed SARL for their advice and help in the present work, and Dr. Jean Bénard PharmD, Ph.D, for his comments and editing.

Compliance with Ethical Standards

Conflict of interest

This work was supported by SATT Ile de France and the Ligue Nationale contre le Cancer, comités d’Ile de France. Baxter freely provided Cyclophosphamid. Second author was a graduate student funded by the Cancéropole Ile-de-France. Sixth and seventh authors are the inventor of patent PCT/EP2012/058219, US-2014-0127180A1.

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Copyright information

© Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2017

Authors and Affiliations

  1. 1.INSERM URM-S 970ParisFrance
  2. 2.Université Paris Descartes, Sorbonne Paris CitéParisFrance
  3. 3.Department of Interventional RadiologyHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance
  4. 4.INSERM, UMR-S 1147ParisFrance
  5. 5.Department of PathologyHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance
  6. 6.Department of BiochimistryHôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de ParisParisFrance

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