title: Differential cytopathology and kinetics of measles oncolysis in two primary B-cell malignancies provides mechanistic insights.
abstract: Clinical trials using vaccine measles virus (MV) as anticancer therapy are already underway. We compared the oncolytic potential of MV in two B-cell malignancies; adult acute lymphoblastic leukemia (ALL, an aggressive leukemia) and chronic lymphocytic leukemia (CLL, an indolent leukemia overexpressing Bcl-2) using patient-derived material. In vitro, distinct cytopathological effects were observed between MV-infected primary ALL and CLL cells, with large multinucleated syncytia forming in ALL cultures compared to minimal cell-to-cell fusion in infected CLL cells. Cell viability and immunoblotting studies confirmed rapid cell death in MV-infected ALL cultures and slower MV oncolysis of CLL cells. In cell lines, overexpression of Bcl-2 diminished MV-induced cell death providing a possible mechanism for the slower kinetic of MV oncolysis in CLL. In vivo, intratumoral MV treatment of established subcutaneous ALL xenografts had striking antitumor activity leading to complete resolution of all tumors. The antitumor activity of MV was also evident in disseminated ALL xenograft models. In summary, both ALL and CLL are targets for MV-mediated lysis albeit with different kinetics. The marked sensitivity of both primary ALL cells and ALL xenografts to MV oncolysis highlights the tremendous potential of MV as a novel replicating-virus therapy for adult ALL.
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: Bella
authors.initials: B
authors.lastname: Patel
authors.forename: Aditi
authors.initials: A
authors.lastname: Dey
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ghorani
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: Yogeshkumar
authors.initials: Y
authors.lastname: Malam
authors.forename: Lena
authors.initials: L
authors.lastname: Rai
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomson
authors.forename: R Gitendra
authors.initials: RG
authors.lastname: Wickremasinghe
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anna Z
authors.initials: AZ
authors.lastname: Castleton
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000628:therapy*; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays