title: CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy.
abstract: We hypothesized that the combination of oncolytic virotherapy with immune checkpoint modulators would reduce tumor burden by direct cell lysis and stimulate antitumor immunity. In this study, we have generated attenuated Measles virus (MV) vectors encoding antibodies against CTLA-4 and PD-L1 (MV-aCTLA-4 and MV-aPD-L1). We characterized the vectors in terms of growth kinetics, antibody expression, and cytotoxicity in vitro. Immunotherapeutic effects were assessed in a newly established, fully immunocompetent murine model of malignant melanoma, B16-CD20. Analyses of tumor-infiltrating lymphocytes and restimulation experiments indicated a favorable immune profile after MV-mediated checkpoint modulation. Therapeutic benefits in terms of delayed tumor progression and prolonged median overall survival were observed for animals treated with vectors encoding anti-CTLA-4 and anti-PD-L1, respectively. Combining systemic administration of antibodies with MV treatment also improved therapeutic outcome. In vivo oncolytic efficacy against human tumors was studied in melanoma xenografts. MV-aCTLA-4 and MV-aPD-L1 were equally efficient as parental MV in this model, with high rates of complete tumor remission (> 80%). Furthermore, we could demonstrate lysis of tumor cells and transgene expression in primary tissue from melanoma patients. The current results suggest rapid translation of combining immune checkpoint modulation with oncolytic viruses into clinical application.
authors.affiliation: 1] Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany [2] Department of Medical Oncology, National Center for Tumor Diseases and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Engeland
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Grossardt
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Rūta
authors.initials: R
authors.lastname: Veinalde
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Bossow
authors.affiliation: Department of Pathology, University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Lutz
authors.affiliation: 1] German Cancer Research Center, Heidelberg, Germany [2] Current address: Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Maryland, USA.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Kaufmann
authors.affiliation: 1] Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany [2] Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Shevchenko
authors.affiliation: 1] Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany [2] Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.affiliation: Department of Pathology, University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: 1] Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany [2] Department of Medical Oncology, National Center for Tumor Diseases and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Guy
authors.initials: G
authors.lastname: Ungerechts
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000378:metabolism*; D005822:Genetic Vectors / Q000008:administration & dosage; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008459:Measles virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen