Delivery of mengovirus-derived RNA replicons into tumoural liver enhances the anti-tumour efficacy of a peripheral peptide-based vaccine.
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.
Couty
Jean-Pierre
JP
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.
Crain
Anne-Marie
AM
Gerbaud
Sylvie
S
Labasque
Marilyne
M
Marchiol
Carmen
C
Fradelizi
Didier
D
Boudaly
Sarah
S
Guettier
Catherine
C
Vignuzzi
Marco
M
van der Werf
Sylvie
S
Escriou
Nicolas
N
Viguier
Mireille
M
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
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D012367:RNA, Viral