Article

Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity.

Department of Clinical and Biological Sciences, University of Turin, Ospedale San Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano, Italy.
Clinical Cancer Research (impact factor: 7.74). 04/2005; 11(5):1941-52. DOI:10.1158/1078-0432.CCR-04-1873 pp.1941-52
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

23rd week
 
adoptive transfer experiments
 
DNA plasmids encoding portions
 
DNA vaccine electroporations
 
Female BALB/c mice transgenic
 
Her-2 receptor electroporated
 
Her-2 spontaneous mammary cancer
 
Her-2 transgenic mice
 
IL-12 augments
 
IL-12 impairs tumor progression
 
immunoglobulin gene knockout transgenic mice
 
markedly that DNA vaccination
 
neoadjuvant interleukin 12
 
neoadjuvant therapy
 
rat Her-2 oncogene inexorably
 
T-cell response elicited
 
transcutaneous electric pulses
 
treatment option
 
vaccine electroporations
 
weekly i.p. injections