Differential Cytopathology and Kinetics of Measles Oncolysis in Two Primary B-cell Malignancies Provides Mechanistic Insights

• Published in: Molecular therapy Vol. 19; no. 6; pp. 1034 - 1040
• Main Authors: Patel, Bella, Dey, Aditi, Ghorani, Ehsan, Kumar, Shaji, Malam, Yogeshkumar, Rai, Lena, Steele, Andrew J, Thomson, Jennifer, Wickremasinghe, R Gitendra, Zhang, Yu, Castleton, Anna Z, Fielding, Adele K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2011; Elsevier Limited; Nature Publishing Group
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Blotting, Western; Cancer therapies; Cell death; Cell Line, Tumor; Cells, Cultured; Cercopithecus aethiops; Hematology; Humans; Infections; Kinetics; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Measles; Measles virus; Measles virus - genetics; Measles virus - physiology; Oncolytic Virotherapy - methods; Original; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Proteins; Tumors; Vaccines; Vero Cells; Viruses; Xenograft Model Antitumor Assays; United Kingdom > UK
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2011.44

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.