Characteristics of carrier cells associated with clinical response in children treated with adenoviral virotherapy administered in autologous marrow-derived mesenchymal cells.

Abstract

e15217 Background: We used oncolytic virotherapy carried by autologous marrow-derived mesenchymal cells to treat children with metastatic/refractory tumors (NCT01844661; 10.1016/j.ymthe.2020.01.019 and 10.1016/j.canlet.2015.11.036). Most patients did not show clinical response while a small group did. Methods: We have carried out a comprehensive study of the transcriptome of this new advanced therapy medicine (ATM) to find determinants that might be associated with clinical outcome. Results: The study of the ATM's transcriptome from a first cohort of patients identified signatures associated to biological processes in the infected carrier cells that distinguished responders from non-responders (viral infection and nucleic acid metabolism; immune regulatory routes; cell-cell adhesion; mitosis; cell metabolism; response to stress; and bone marrow fibrosis). Next, we used an approach based on systems biology and neural networks to identify candidates responsible for the differences found in gene expression signatures. We then validated the identified candidates using samples obtained from a second independent cohort of patients, by quantitative PCR and ELISA. Mesenchymal cells of the responding patients expressed significantly lower levels of the MAVS and NDRG1 genes compared with those of the non-responders after oncolytic adenoviral infection. Both genes are related to cellular antiviral responses and cellular metabolism. Accordingly, mesenchymal cells of responders produced significantly lower amounts of IL-6 and CCL-2 than non-responders’ cells. Conclusions: These results point to possible pretreatment biomarkers and the possibility of optimizing a universal version of the carrier cells for the oncolytic virus in this new ATM.