Adenovirus-enhanced receptor-mediated transferrinfection for the generation of tumor vaccines.
Cancer vaccines are genetically modified tumor cells that, by cytokine secretion or by expression of costimulatory molecules, are capable of mobilizing the host's immune system to destroy tumor cells. We have used adenovirus-enhanced transferrinfection (AVET) for the generation of cancer vaccines. This is a highly efficient method to deliver various genes into a large proportion of tumor cells, making further selection unnecessary. We found in the mouse M-3 melanoma model that two consecutive vaccinations with transfected cells secreting IL-2 protect animals from tumor development by a subsequent challenge, and result in long-lasting tumor-specific immunity dependent on both CD4+ and CD8+ T cells. Patterns of lymphocyte recirculation and the need for CD4+ T cells indicated that the role of IL-2 is not merely local 'replacement of help', as has been proposed before. Instead, our findings suggest a three-stage process for the generation of effector T cells after vaccination with IL-2 secreting tumor cells: (1) tumor antigen uptake and processing at the site of injection by APCs, (2) migration of APCs into the regional draining lymph nodes where T-cell priming occurs, and (3) recirculation of activated cytotoxic T cells, that recognize and eliminate distant tumor cells. This model also implies that allogeneic tumor cells or synthetic tumor antigens may be used with success in future cancer vaccines.
Schweighoffer
T
T
Research Institute of Molecular Pathology (IMP), Wien, Austria. tamas@aimp.una.ac.at
Berger
M
M
Buschle
M
M
Schmidt
W
W
Birnstiel
M L
ML
D000256:Adenoviridae; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000096:biosynthesis*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D011107:Polylysine; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000379:methods*; D014168:Transferrin / Q000096:biosynthesis
D019496:Cancer Vaccines; D007376:Interleukin-2; D014168:Transferrin; D011107:Polylysine