title: Delivery of mengovirus-derived RNA replicons into tumoural liver enhances the anti-tumour efficacy of a peripheral peptide-based vaccine.
abstract: Hepatocellular carcinoma is a deadly cancer with growing incidence for which immunotherapy is one of the most promising therapeutic approach. Peptide-based vaccines designed to induce strong, sustained CD8+ T cell responses are effective in animal models and cancer patients. We demonstrated the efficacy of curative peptide-based immunisation against a unique epitope of SV40 tumour antigen, through the induction of a strong CD8+ T cell-specific response, in our liver tumour model. However, as in human clinical trials, most tumour antigen epitopes did not induce a therapeutic effect, despite inducing strong CD8+ T cell responses. We therefore modified the tumour environment to enhance peptide-based vaccine efficacy by delivering mengovirus (MV)-derived RNA autoreplicating sequences (MV-RNA replicons) into the liver. The injection of replication-competent RNA replicons into the liver converted partial tumour regression into tumour eradication, whereas non-replicating RNA had no such effect. Replicating RNA replicon injection induced local recruitment of innate immunity effectors (NK and NKT) to the tumour and did not affect specific CD8+ T cell populations or other myelolymphoid subsets. The local delivery of such RNA replicons into tumour stroma is therefore a promising strategy complementary to the use of peripheral peptide-based vaccines for treating liver tumours.
authors.affiliation: Institut Cochin, Département Endocrinologie-Métabolisme et Cancer, Institut National de la Santé et de la Recherche Médicale INSERM U567, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Couty
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Crain
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerbaud
authors.forename: Marilyne
authors.initials: M
authors.lastname: Labasque
authors.forename: Carmen
authors.initials: C
authors.lastname: Marchiol
authors.forename: Didier
authors.initials: D
authors.lastname: Fradelizi
authors.forename: Sarah
authors.initials: S
authors.lastname: Boudaly
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.forename: Marco
authors.initials: M
authors.lastname: Vignuzzi
authors.forename: Sylvie
authors.initials: S
authors.lastname: van der Werf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Escriou
authors.forename: Mireille
authors.initials: M
authors.lastname: Viguier
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008574:Mengovirus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology; D012367:RNA, Viral / Q000276:immunology*; D012093:Replicon / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D012367:RNA, Viral