title: Microsphere priming facilitates induction of potent therapeutic T-cell immune responses against autochthonous liver cancers.
abstract: Immunotherapy of solid tumors is often hampered by the low frequency of tumor-specific T cells elicited by current vaccination strategies. Here, we describe a prime-boost vaccination protocol based on the administration of antigen conjugated to poly-lactic-co-glycolic acid (PLGA) microspheres followed by booster vaccination with Listeria monocytogenes vectors, which rapidly generates potent immune responses within two weeks. Compared with conventional vaccination with antigen-pulsed dendritic cells, the use of PLGA microspheres resulted in immune responses of significantly higher magnitude, which could be further enhanced via coinjection of TLR 3 agonists. In an immunocompetent model of subcutaneous hepatocellular carcinoma, PLGA/Listeria vaccination resulted in complete remission of established tumors and prolonged survival. To further test the efficacy of the novel vaccination for the treatment of solid tumors, we developed an orthotopic liver cancer model based on the injection of transposon-flanked plasmids expressing oncogenes and model antigens. In this transgenic mouse model of liver cancer, PLGA/Listeria vaccination resulted in eradication of liver tumors, long-term survival of animals and establishment of stable cancer-specific memory CD8(+) T-cell populations. Therefore, combined PLGA/Listeria vaccination holds promise as a novel immunotherapeutic option for the treatment of solid cancers and as a means to boost the therapeutic efficacy of established cancer vaccines.
authors: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors: Benjamin
authors: B
authors: Brinkhoff
authors: Dmitrij
authors: D
authors: Ostroumov
authors: Jessica
authors: J
authors: Heemcke
authors: Norman
authors: N
authors: Woller
authors: Engin
authors: E
authors: Gürlevik
authors: Michael P
authors: MP
authors: Manns
authors: Thomas
authors: T
authors: Longerich
authors: Lars
authors: L
authors: Zender
authors: John T
authors: JT
authors: Harty
authors: Stefan
authors: S
authors: Kubicka
authors: Florian
authors: F
authors: Kühnel
authors: Thomas C
authors: TC
authors: Wirth
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007117:Immunization, Secondary; D007167:Immunotherapy / Q000379:methods; D019344:Lactic Acid / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016019:Survival Analysis; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D051196:Toll-Like Receptor 3; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; D011070:Poly I-C
keywords: Immunotherapy; Liver cancer; Microspheres; Vaccination