Immunoprevention of HER-2/neu transgenic mammary carcinoma through an interleukin 12-engineered allogeneic cell vaccine.
This study evaluated the ability of cytokine-engineered allogeneic (H-2(q)) HER-2/neu-positive cells to prevent tumor development in mammary cancer-prone virgin female BALB/c (H-2(d)) mice transgenic for the transforming rat HER-2/neu oncogene (BALB-neuT mice). Repeated vaccinations with cells engineered to release interleukin (IL)-2, IL-12, IL-15, or IFN-gamma showed that IL-12-engineered cell vaccines had the most powerful immunopreventive activity, with >80% of 1-year-old BALB-neuT mice free of tumors. On the contrary all of the untreated mice and all of the mice vaccinated with IL-12-engineered cells lacking either HER-2/neu or allogeneic antigens developed mammary carcinomas within 22 or 33 weeks, respectively. Whole mount, histology, immunohistochemistry, and gene expression profile analysis showed that vaccination with IL-12-engineered cells maintained 26-week mammary glands free of neoplastic growth, with a gene expression profile that clustered with that of untreated preneoplastic glands. The IL-12-engineered cell vaccine elicited a high production of IFN-gamma and IL-4 and a strong anti-HER-2/neu antibody response. Immune protection was lost or markedly impaired in BALB-neuT mice lacking IFN-gamma or antibody production, respectively. The protection afforded by the IL-12-engineered cell vaccine was equal to that provided by the systemic administration of recombinant IL-12 in combination with HER-2/neu H-2(q) cell vaccine. However, IL-12-engineered cell vaccine induced much lower circulating IL-12 and IFN-gamma, and therefore lower potential side effects and systemic toxicity.
De Giovanni
Carla
C
Department of Experimental Pathology, University of Bologna, Bologna. carla.degiovanni@unibo.it
Nicoletti
Giordano
G
Landuzzi
Lorena
L
Astolfi
Annalisa
A
Croci
Stefania
S
Comes
Alberto
A
Ferrini
Silvano
S
Meazza
Raffaella
R
Iezzi
Manuela
M
Di Carlo
Emma
E
Musiani
Piero
P
Cavallo
Federica
F
Nanni
Patrizia
P
Lollini
Pier-Luigi
PL
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D014611:Vaccination
D019496:Cancer Vaccines; D016207:Cytokines; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases