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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    ABSTRACT: New local treatments based on electromagnetic fields have been developed as non-surgical and minimally invasive treatments of tumors. In particular, short electric pulses can induce important non-thermal changes in cell physiology, especially the permeabilization of the cell membrane. The aim of this review is to summarize the present data on the electroporation-based techniques: electrochemotherapy (ECT), nanosecond pulsed electric fields (nsPEFs), and irreversible electroporation (IRE). ECT is a safe, easy, and efficient technique for the treatment of solid tumors that uses cell-permeabilizing electrical pulses to enhance the activity of a non-permeant (bleomycin) or low permeant (cisplatin) anticancer drug with a very high intrinsic cytotoxicity. The most interesting feature of ECT is its unique ability to selectively kill tumor cells without harming normal surrounding tissue. ECT is already used widely in the clinics in Europe. nsPEFs could represent a drug free, purely electrical cancer therapy. They allow the inhibition of tumor growth, and interestingly, nsPEF can target intracellular organelles. However, many questions remain on the mechanism of action of these pulses. Finally, IRE is a new ablation procedure using pulses that provoke the permanent permeabilization of the cells resulting in their death. This technique does not result in any thermal effect, which is its main advantage in current physical ablation technologies. For both the nsPEF and the IRE, the preservation of the normal tissue, which is characteristic of ECT, has not yet been shown and their safety and efficacy still have to be investigated thoroughly in vivo and in the clinics. Bioelectromagnetics. © 2011 Wiley-Liss, Inc.
    Bioelectromagnetics 02/2012; 33(2). DOI:10.1002/bem.20692 · 1.86 Impact Factor
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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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    ABSTRACT: It has been frequently reported that gp96 acts as a strong biologic adjuvant. Some studies have even investigated adjuvant activity of the gp96 C- or N-terminal domain. The controversy surrounding adjuvant activity of gp96 terminal domains prompted us to compare adjuvant activity of gp96 C- or N-terminal domain toward Her2/neu, as DNA vaccine in a Her2/neu-positive breast cancer model. To do so, mice were immunized with DNA vaccine consisting of transmembrane and extracellular domain (TM + ECD) of rat Her2/neu alone or fused to N- or C-terminal domain of gp96. Treatment with Her2/neu fused to N-terminal domain of gp96 resulted in tumor progression, compared to the groups vaccinated with pCT/Her2 or pHer2. Immunological examination revealed that treatment with Her2/neu fused to N-terminal domain of gp96 led to significantly lower survival rates, higher interferon-γ secretion, and induced infiltration of CD4(+)/CD8(+) cells to the tumor site. However, it could not induce cytotoxic T lymphocyte activity, did not decrease regulatory T cell percentage at the tumor site, and eventually led to tumor progression. Our results reveal that gp96 N-terminal domain does not have adjuvant activity toward Her2/neu. It is also proposed that adjuvant activity and the resultant immune response of gp96 terminal domains may be directed by the antigen applied.
    Cell Stress and Chaperones 02/2011; 16(4):449-57. DOI:10.1007/s12192-011-0258-6 · 2.54 Impact Factor
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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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    ABSTRACT: Heat-shock proteins have biochemical and immunological roles in chaperoning/signaling and activation of innate and adaptive immune responses, respectively. Their effect on the immune response is due to a phenomenon known as cross-priming of antigen, in which exogenous antigens are presented via MHC class I by antigen presenting cells. GP96 exerts adjuvant activity with some viral and bacterial antigens when applied in the form of a DNA vaccine. In this study, animals with Her2-expressing tumors were vaccinated by co-administration of GP96+ Her2/neu DNA vaccines. Analyses of the immune response, 2 weeks after the last immunization revealed decreased CD4+ CD25+ Foxp3+ naturally occurring regulatory T cells (Tregs) at the tumor site and increased IFN-γ/IL-4 level. Nevertheless, the graph of tumor size demonstrated a bi-phasic pattern in which partial control of tumor progression initially occurred, but finally its effectiveness was inversely affected by tumor size.
    Cell Stress and Chaperones 11/2010; 15(6):977-84. DOI:10.1007/s12192-010-0208-8 · 2.54 Impact Factor
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