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Cancer Immunol Res ; 2(12): 1163-74, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25168392

RESUMO

Effector T-cell access to tumor tissue is a limiting step for clinical efficacy of antigen-specific T cell-based immunotherapies. Ectopic mouse tumor models, in which a subcutaneously (s.c.) implanted tumor is treated with s.c. or intramuscular therapeutic immunization, may not be optimal for targeting effector T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to evaluate the impact of injection routes on therapeutic efficacy of a Modified Vaccinia virus Ankara viral vector expressing the human mucin 1 tumor-associated xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of MVA-MUC1 displayed enhanced efficacy when compared with s.c. injection. Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9 agonist. In all cases, infiltration of tumor-bearing kidney by CD8(+) lymphocytes was associated with control of tumor growth. Biodistribution experiments indicate that, following i.v. injection, MVA-encoded antigens are quickly expressed in visceral organs and, in particular, in splenic antigen-presenting cells, compared with those following s.c. injection. This appears to result in a faster generation of MUC1-specific CD8(+) T cells. Lymphocytes infiltrating tumor-bearing kidneys are characterized by an effector memory phenotype and express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was associated with a modification of the tumor microenvironment toward a Th1-type immune response and recruitment of activated lymphocytes. This study supports the clinical evaluation of MVA-based immunotherapies via the i.v. route.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vetores Genéticos/genética , Neoplasias/imunologia , Neoplasias/terapia , Receptor Toll-Like 9/agonistas , Vaccinia virus/genética , Animais , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Humanos , Imunofenotipagem , Imunoterapia , Injeções Intravenosas , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Mucina-1/genética , Mucina-1/imunologia , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/farmacologia , Fenótipo , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
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