Article

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

Wayne State University, Detroit, Michigan, United States
Clinical Cancer Research (Impact Factor: 8.19). 04/2005; 11(5):1941-52. DOI: 10.1158/1078-0432.CCR-04-1873
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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Available from: Augusto Amici, May 05, 2015
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    • "For example, the electrotransfer of genes coding for interleukin-12 was tested for the treatment of advanced melanoma metastases [Daud et al., 2008]. Classical electroporation could be equally useful for DNA vaccination against breast cancer [Spadaro et al., 2005] or hepatitis C [Arcuri et al., 2008], even though this application is not yet in the clinics. The pulse conditions still have to be optimized for different tissues to increase the gene expression [André et al., 2008]. "
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    • "New strategies have been applied to enhance both the quality and quantity of the immune response against Her2- expressing tumors. Some studies have used the Her2 gene with cytokine or other molecules such as heat shock proteins (HSPs) involved in regulation of the immune response to enhance the potency of Her2/neu DNA vaccines (Cappello et al. 2003; Chang et al. 2004; Dela Cruz et al. 2005; Disis et al. 2003; Lin et al. 2004; Orlandi et al. 2007; Spadaro et al. 2005; Wei et al. 1999). gp96 is a member of the HSP90 family and plays important roles in innate and adaptive immune responses, besides protein folding and assembly (Srivastava 2002; Nicchitta 2003). "
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    • "However, the potency of Her2/neuDNA vaccine still needs to be improved. Some investigators co-administered constructs containing cytokine or co-stimulatory molecule genes and others utilized fusion technology to enhance the potency of Her2/neu DNA vaccines (Dela Cruz et al. 2005; Kim et al. 2005; Lin et al. 2004; Spadaro et al. 2005). Heat shock proteins (HSPs) have so far been regarded as potent adjuvants in immunotherapy of cancers and infectious disease (Binder 2008). "
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