Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma
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Lidia Franco-Luzón1, África González-Murillo2,3,5, Cristina Alcántara-Sánchez3, Lorena García-García3, Maryam Tabasi3, Ana Luis Huertas4, Louis Chesler6 and Manuel Ramírez2,3,5
1 Fundación Oncohematología Infantil, Madrid, Spain
2 Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
3 Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
4 Servicio de Cirugía, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
5 Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
6 Paediatric Solid Tumour Biology and Therapeutics Team, Division of Clinical Studies and Cancer Therapeutics Division, The Institute of Cancer Research, Sutton, Surrey, UK
Keywords: oncolytic virotherapy; neuroblastoma; mesenchymal stem cells; tumor microenvironment; immune response
Received: July 16, 2019 Accepted: October 21, 2019 Published: January 28, 2020
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.
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