title: Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity.
abstract: Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL.
authors.affiliation: Department of Hematology, University College London, London, United Kingdom;
authors.forename: Anna
authors.initials: A
authors.lastname: Castleton
authors.forename: Aditi
authors.initials: A
authors.lastname: Dey
authors.forename: Brendan
authors.initials: B
authors.lastname: Beaton
authors.forename: Bella
authors.initials: B
authors.lastname: Patel
authors.forename: Anne
authors.initials: A
authors.lastname: Aucher
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology*; D008459:Measles virus; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays