title: Sequential administration of a MVA-based MUC1 cancer vaccine and the TLR9 ligand Litenimod (Li28) improves local immune defense against tumors.
abstract: TG4010 is an immunotherapeutic vaccine based on Modified Vaccinia virus Ankara (MVA) encoding the human tumor-associated antigen MUC1 and human IL-2. In combination with first-line standard of care chemotherapy in advanced metastatic non-small-cell lung cancer (NSCLC), repeated subcutaneous injection of TG4010 improved progression-free survival in phase 2b clinical trials. In preclinical tumor models, MVATG9931, the research version of TG4010, conferred antigen-specific responses against the weak antigen human MUC1. The combination of a suboptimal dose of MVATG9931 and the type B TLR9 ligand Litenimod (Li28) markedly increased survival in a subcutaneous RMA-MUC1 tumor model compared to the treatment with MVATG9931 or Li28 alone. The requirements for this protection were (i) de novo synthesis of MUC1, (ii) Li28 delivered several hours after MVATG9931 at the same site, (iii) at least two vaccination cycles, and (iv) implantation of MUC1-positive tumor cells in the vicinity to the vaccination site. Subcutaneously injected MVATG9931 allowed transient local gene expression and induced the local accumulation of MCP-1, RANTES, M-CSF, IL-15/IL-15R and IP-10. After repeated injection, CD4+and CD8+T lymphocytes, B lymphocytes, NK cells, pDCs, neutrophils, and macrophages accumulated around the injection site, local RANTES levels remained high. Delayed injection of Li28 into this environment, led to further accumulation of macrophages, the secretion of IL-18 and IL-1 beta, and an increase of the percentage of activated CD69+NK cell. Combination treatment augmented the number of activated CD86+DCs in the draining lymph nodes and increased the percentage of KLRG1+CD127-CD8+T cells at the injection site. In vivo depletion of macrophages around the injection site by Clodronate liposomes reduced local IL-18 levels and diminished survival rates significantly. Thus, sequential administration of MVATG9931 and Li28 improves local innate and adaptive immune defense against tumors, arguing for intratumoral delivery of this peculiar sequential combination therapy.
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Schaedler
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Remy-Ziller
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Hortelano
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kehrer
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Claudepierre
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gatard
authors.affiliation: Institut of Molecular Medicine, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jakobs
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
authors.affiliation: Laboratoire de Recherches Biochirurgicales, Université Paris Descartes, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France.
authors.forename: Antoine F
authors.initials: AF
authors.lastname: Carpentier
authors.affiliation: TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France. Electronic address: rittner@transgene.fr.
authors.forename: Karola
authors.initials: K
authors.lastname: Rittner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018396:Mucin-1 / Q000276:immunology*; D009369:Neoplasms / Q000628:therapy*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016896:Treatment Outcome; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D004337:Drug Carriers; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; C518275:TG4010; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9
keywords: Cancer vaccine; IL-18; Innate immunity; Macrophages; Modified vaccinia virus Ankara; Toll-like receptor