Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity.
OBJECTIVE
Whereas neoadjuvant therapy is emerging as a treatment option in early primary breast cancer, no data are available on the use of antiangiogenic and immunomodulatory agents in a neoadjuvant setting. In a model of Her-2 spontaneous mammary cancer, we investigated the efficacy of neoadjuvant interleukin 12 (IL-12) followed by "immune-surgery" of the residual tumor.


METHODS
Female BALB/c mice transgenic for the rat Her-2 oncogene inexorably develop invasive carcinomas in all their mammary glands by the 23rd week of age. Mice with multifocal in situ carcinomas received four weekly i.p. injections of 100 ng IL-12 followed by a 3-week rest. This course was given four times. A few mice additionally received DNA plasmids encoding portions of the Her-2 receptor electroporated through transcutaneous electric pulses.


RESULTS
The protection elicited by IL-12 in combination with two DNA vaccine electroporations kept 63% of mice tumor-free. Complete protection of all 1-year-old mice was achieved when IL-12-treated mice received four vaccine electroporations. Pathologic findings, in vitro tests, and the results from immunization of both IFN-gamma and immunoglobulin gene knockout transgenic mice and of adoptive transfer experiments all show that IL-12 augments the B- and T-cell response elicited by vaccination and slightly decreases the number of regulatory T cells. In addition, IL-12 strongly inhibits tumor angiogenesis.


CONCLUSIONS
In Her-2 transgenic mice, IL-12 impairs tumor progression and triggers innate immunity so markedly that DNA vaccination becomes effective at late points in time when it is ineffective on its own.
Spadaro
Michela
M
Department of Clinical and Biological Sciences, University of Turin, Ospedale San Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano, Italy.
Ambrosino
Elena
E
Iezzi
Manuela
M
Di Carlo
Emma
E
Sacchetti
Pamela
P
Curcio
Claudia
C
Amici
Augusto
A
Wei
Wei-Zen
WZ
Musiani
Piero
P
Lollini
Pier-Luigi
PL
Cavallo
Federica
F
Forni
Guido
G
D000818:Animals; D019496:Cancer Vaccines; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology*; D018274:Electroporation; D005260:Female; D018734:Genes, erbB-2; D007107:Immune System / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020360:Neoadjuvant Therapy; D010957:Plasmids / Q000235:genetics
D019496:Cancer Vaccines; D018664:Interleukin-12