title: Influence of carrier cells on the clinical outcome of children with neuroblastoma treated with high dose of oncolytic adenovirus delivered in mesenchymal stem cells.
abstract: We report here our clinical experience of a program of compassionate use of Celyvir--autologous marrow-derived mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus--for treating children with advanced metastatic neuroblastoma. Children received weekly doses of Celyvir with no concomitant treatments. The tolerance was excellent, with very mild and self-limited viral-related symptoms. Patients could be distinguished based on their response to therapy: those who had a clinical response (either complete, partial or stabilization) and those who did not respond. We found differences between patients who responded versus those who did not when analyzing their respective MSCs, at the expression levels of adhesion molecules (CCR1, CXCR1 and CXCR4) and in migration capacities in transwell assays, and in immune-related molecules (IFNγ, HLA-DR). These results suggest interpatient differences in the homing and immune modulation capacities of the therapy administered. In addition, the pretherapy immune T cell status and the T effector response were markedly different between responders and non-responders. We conclude that multidoses of Celyvir have an excellent safety profile in children with metastatic neuroblastoma. Intrinsic patients' and MSCs' factors appear to be related to clinical outcome.
authors.affiliation: Fundación para la Investigación Biomédica, Hospital Universitario Niño Jesús, Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.affiliation: Fundación Oncohematología Infantil, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Franco-Luzón
authors.affiliation: Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Ruano
authors.affiliation: Fundación para la Investigación Biomédica, Hospital Universitario Niño Jesús, Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: África
authors.initials: Á
authors.lastname: González-Murillo
authors.affiliation: Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Arantzazu
authors.initials: A
authors.lastname: Alfranca
authors.affiliation: Anatomía Patológica, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Casco
authors.affiliation: Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Lassaletta
authors.affiliation: Microbiología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alonso
authors.affiliation: Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Luís
authors.initials: L
authors.lastname: Madero
authors.affiliation: Institut Català d'Oncologia-IDIBELL, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Alemany
authors.affiliation: Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Castro
authors.affiliation: Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain. Electronic address: manuel.ramirez@salud.madrid.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramírez
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity*; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D057176:Compassionate Use Trials; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000556:secondary / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000472:pathogenicity*; D010641:Phenotype; D054389:Receptors, CCR1 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D013030:Spain; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014779:Virus Replication
chemical_list: D015415:Biomarkers; C515300:CCR1 protein, human; C527276:CXCR4 protein, human; D006684:HLA-DR Antigens; C573415:IFNG protein, human; D054389:Receptors, CCR1; D019718:Receptors, CXCR4; D023062:Receptors, Interleukin-8A; D007371:Interferon-gamma
keywords: Cell migration; Immune response; Mesenchymal stem cells; Neuroblastoma; Oncolytic virotherapy