Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma.

Abstract

Celyvir (autologous mesenchymal cells -MSCs- that carry an oncolytic adenovirus) is a new therapeutic strategy for metastatic tumors developed by our research group over the last decade. There are limitations for studying the immune effects of human oncolytic adenoviruses in murine models since these viruses do not replicate naturally in these animals. The use of xenografts in immunodeficient mice prevent assessing important clinical aspects of this therapy such as the antiadenoviral immune response or the possible intratumoral immune changes, both of tumor infiltrating leukocytes and of the microenvironment. In our strategy, the presence of MSCs in the medicinal product adds an extra level of complexity. We present here a murine model that overcomes many of these limitations. We found that carrier cells outcompeted intravenous administration of naked particles in delivering the oncolytic virus into the tumor masses. The protection that MSCs could provide to the oncolytic adenovirus did not preclude the development of an antiadenoviral immune response. However, the presence of circulating antiadenoviral antibodies did not prevent changes detected at the tumor masses: increased infiltration and changes in the quality of immune cells per unit of tumor volume, and a less protumoral and more inflammatory profile of the tumor microenvironment. We believe that the model described here will enable the study of crucial events related to the immune responses affecting both the medicinal product and the tumor.