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Viruses 2014, 6(8), 3080-3096;

Locally-Delivered T-Cell-Derived Cellular Vehicles Efficiently Track and Deliver Adenovirus Delta24-RGD to Infiltrating Glioma

Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Einthovenweg 20, 2333 ZC, The Netherlands
Molecular Neurosurgery Laboratory, Brain Tumor Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Laboratory of Experimental Tumor Immunology, Department Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GE, The Netherlands
Author to whom correspondence should be addressed.
Received: 23 April 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published: 12 August 2014
(This article belongs to the Special Issue Adenoviral Vectors)
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Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma. Recent publications have demonstrated the advantages of shielding viral particles within cellular vehicles (CVs), which can be targeted towards the tumor microenvironment. Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma. The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro. The effect of intraparenchymal and tail vein injections on intratumoral virus distribution and overall survival was addressed in an orthotopic glioma stem cell (GSC)-based xenograft model. Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs. Delta24-RGD dosing and incubation time were found to influence the migratory ability of T-cells towards GSCs. Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones. This occurred after injection into the ipsilateral hemisphere, as well as into the non-tumor-bearing hemisphere. We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007). Systemic administration of virus-loaded T-cells resulted in intratumoral viral delivery, albeit at low levels. Based on these findings, we conclude that T-cell-based CVs are a feasible approach to local Delta24-RGD delivery in glioblastoma, although efficient systemic targeting requires further improvement. View Full-Text
Keywords: glioblastoma; oncolytic; cellular vehicles; GSC; T-cell therapy; virotherapy; Delta24-RGD glioblastoma; oncolytic; cellular vehicles; GSC; T-cell therapy; virotherapy; Delta24-RGD

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Balvers, R.K.; Belcaid, Z.; Van den Hengel, S.K.; Kloezeman, J.; De Vrij, J.; Wakimoto, H.; Hoeben, R.C.; Debets, R.; Leenstra, S.; Dirven, C.; Lamfers, M.L. Locally-Delivered T-Cell-Derived Cellular Vehicles Efficiently Track and Deliver Adenovirus Delta24-RGD to Infiltrating Glioma. Viruses 2014, 6, 3080-3096.

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