RESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Ácido Láctico/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Microesferas , Animais , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Citocinas/imunologia , Citocinas/metabolismo , Citometria de Fluxo , Imunização Secundária , Imunoterapia/métodos , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/microbiologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Poli I-C/imunologia , Poli I-C/farmacologia , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Análise de Sobrevida , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/imunologia , Resultado do Tratamento , Vacinação/métodosRESUMO
Efficient immunotherapy relies on the rapid generation of elevated amounts of cancer-specific T lymphocytes. We have recently demonstrated that both rapid and potent tumor-targeting immune responses can be induced with a heterologous prime-boost regimen consisting of poly-lactic co-glycolic acid (PLGA) microsphere-based immunization followed by Listeria monocytogenes infection.