Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model

Esther Rincón,Ramón Alemany,Maciej S Lesniak,Lingjiao Zhang,Javier García-Castro,Arantzazu Alfranca,Raul Andrés Gil Hoyos,Yu Han,Deepak Kanojia,Miguel Ángel Rodríguez-Milla,Teresa Cejalvo

doi:10.18632/oncotarget.17557

Abstract

Oncolytic virotherapy represents a promising alternative for cancer treatment; however, viral delivery to the tumor represents a major challenge. Mesenchymal stem cells (MSCs) chemotax to tumors, and can serve as a viral delivery tool. Previously, we demonstrated antitumor therapeutic efficacy for mesenchymal stem cells (MSCs) infected with the oncolytic human adenovirus ICOVIR5 (Celyvir) for treatment of neuroblastoma patients. Given the lack of suitable immunocompetent preclinical models, the mechanism underlying Celyvir antitumor activity remains unknown. In this study, we used the syngeneic murine CMT64 cell line as a human adenovirus-semi-permissive tumor model and demonstrate the homing capacity of mouse Celyvir (mCelyvir) to CMT64 tumors. We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t. ICOVIR5 alone. Interestingly, the superior therapeutic effect of the combined therapy was associated with a higher tumor infiltration of CD8+ and CD4+ T cells. Our findings suggest that the use of MSCs as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, not only by driving the adenovirus to tumors, but also through their potential to recruit T cells.

Highlights

A correlation between the level of immune cell infiltration and the clinical outcome has been detected in many cancers [1]
We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t
Our findings suggest that the use of Mesenchymal stem cells (MSCs) as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, by driving the adenovirus to tumors, and through their potential to recruit T cells

Summary

Introduction

A correlation between the level of immune cell infiltration and the clinical outcome has been detected in many cancers [1]. While antitumor immunotherapy has primarily focused on activating T cells and inhibiting immune checkpoints [2], oncolytic viruses may represent an alternative strategy for cytoreduction of tumors. Do oncolytic viruses combat tumors via direct lysis and/or vascular attack, but they potently activate the adaptive and innate immune responses [3]. Mesenchymal stem cells (MSCs) have the intrinsic capability to migrate to solid tumor and have been employed to deliver anti-cancer agents, including oncolytic Ad, to the tumor. This method reduces systemic side effects, and promotes effective local anti-tumor activity. The ability of MSCs to modulate the immune system has been suggested to be crucial for their benefits in antitumor strategies [10,11,12,13]

Methods

Results

Conclusion