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

Viruses

Rutger K. Balvers²  Zineb Belcaid²  Sanne K. van den Hengel¹  Jenneke Kloezeman²  Jeroen de Vrij²  Hiroaki Wakimoto³  Rob C. Hoeben¹  Reno Debets⁴  Sieger Leenstra²  Clemens Dirven² 

[1] Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Einthovenweg 20, 2333 ZC, The Netherlands; E-Mails:;Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands; E-Mails:;Molecular Neurosurgery Laboratory, Brain Tumor Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; E-Mail:;Laboratory of Experimental Tumor Immunology, Department Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GE, Netherlands; E-Mail:

关键词: glioblastoma;    oncolytic;    cellular vehicles;    GSC;    T-cell therapy;    virotherapy;    Delta24-RGD;   

DOI  :  10.3390/v6083080

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.