title: Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia.
abstract: The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-α (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: C
authors: C
authors: Parrish
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: G B
authors: GB
authors: Scott
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: G
authors: G
authors: Migneco
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: K J
authors: KJ
authors: Scott
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: L P
authors: LP
authors: Steele
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: E
authors: E
authors: Ilett
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: E J
authors: EJ
authors: West
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: K
authors: K
authors: Hall
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: P J
authors: PJ
authors: Selby
authors: St James's University Hospital, Leeds, UK.
authors: D
authors: D
authors: Buchanan
authors: St James's University Hospital, Leeds, UK.
authors: A
authors: A
authors: Varghese
authors: Antibody and Vaccine Group, Cancer Sciences Unit, Southampton University, General Hospital, Southampton, UK.
authors: M S
authors: MS
authors: Cragg
authors: Oncolytics Biotech Inc., Calgary, AB, Canada.
authors: M
authors: M
authors: Coffey
authors: Experimental Haematology, LICAP, University of Leeds, Leeds, UK.
authors: P
authors: P
authors: Hillmen
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: A A
authors: AA
authors: Melcher
authors: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, St James's University Hospital, Leeds, UK.
authors: F
authors: F
authors: Errington-Mais
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use; D016130:Immunophenotyping; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000276:immunology*; D008875:Middle Aged; D009367:Neoplasm Staging; D050504:Oncolytic Viruses / Q000276:immunology*; D000069283:Rituximab / Q000276:immunology* / Q000627:therapeutic use*; D014779:Virus Replication
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D000069283:Rituximab