title: Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control tumor growth upon combinatorial treatment with a TLR9 agonist.
abstract: Effector T-cell access to tumor tissue is a limiting step for clinical efficacy of antigen-specific T cell-based immunotherapies. Ectopic mouse tumor models, in which a subcutaneously (s.c.) implanted tumor is treated with s.c. or intramuscular therapeutic immunization, may not be optimal for targeting effector T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to evaluate the impact of injection routes on therapeutic efficacy of a Modified Vaccinia virus Ankara viral vector expressing the human mucin 1 tumor-associated xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of MVA-MUC1 displayed enhanced efficacy when compared with s.c. injection. Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9 agonist. In all cases, infiltration of tumor-bearing kidney by CD8(+) lymphocytes was associated with control of tumor growth. Biodistribution experiments indicate that, following i.v. injection, MVA-encoded antigens are quickly expressed in visceral organs and, in particular, in splenic antigen-presenting cells, compared with those following s.c. injection. This appears to result in a faster generation of MUC1-specific CD8(+) T cells. Lymphocytes infiltrating tumor-bearing kidneys are characterized by an effector memory phenotype and express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was associated with a modification of the tumor microenvironment toward a Th1-type immune response and recruitment of activated lymphocytes. This study supports the clinical evaluation of MVA-based immunotherapies via the i.v. route.
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gatard-Scheikl
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kintz
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Gantzer
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Schaedler
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Karola
authors.initials: K
authors.lastname: Rittner
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cochin
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, Equipe de Biovectorologie, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch-Graffenstaden, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France. preville@transgene.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D007275:Injections, Intravenous; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D010641:Phenotype; D014018:Tissue Distribution; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D019496:Cancer Vaccines; D018396:Mucin-1; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9