Abstract
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.
Highlights
Glioblastoma is the most frequently diagnosed primary brain tumor in adults, with a median survival of only 15 months after the initial diagnosis [1]
Delivery of Delta24-RGD by Jurkat T-cell-cellular vehicles (CVs) was assessed in a series of in vitro assays
Additional hexon staining was detected in the tumor-bearing hemisphere in small tumor colonies at the invading margins of the tumor. These results demonstrate the intraparenchymal tropism of CV to the tumor, subsequently resulting in the in vivo transfer of oncolytic adenovirus to distant tumor cells (Figure 4E)
Summary
Glioblastoma is the most frequently diagnosed primary brain tumor in adults, with a median survival of only 15 months after the initial diagnosis [1]. Despite the extensive scientific progress that has been made into the molecular characteristics of glioblastoma, patient prognosis has remained virtually unaltered. Translational research is warranted for the development of new therapeutic agents. Oncolytic virotherapy has been extensively studied for the treatment of glioblastoma and has proven to be a safe and feasible strategy from preclinical [2,3] and clinical safety studies [4,5]. Delta24-RGD is a conditionally replicating oncolytic adenovirus that has demonstrated therapeutic efficacy in preclinical models of glioblastoma [6,7,8].
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