Human ErbB-2 (Her-2) Transgenic Mice: A Model System for Testing Her-2 Based Vaccines

Piechocki, Marie P.; Ho, Ye Shih; Pilon, Shari A.; Wei, Wei Zen

doi:10.4049/jimmunol.171.11.5787

Cited by 109 publications

(115 citation statements)

References 27 publications

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“…In patients with malignant disorders, NK cell function can be impaired, resulting in a reduced proliferative response and reduced cytotoxic activity (29). Consequently, it may not be possible to generate suitable autologous effector cells in all cases where this is the case.…”

Section: Discussionmentioning

confidence: 99%

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Liu

Yang

Sun³

et al. 2014

Oncol Rep

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Abstract. The natural killer cell line NK-92 shows great cytotoxicity against various types of cancer. Several types of solid tumor cells, however, can effectively resist NK-mediated lysis by interaction of major histocompatibility complex (MHC) molecules with NK cell inhibitory receptors. To generate a eukaryotic expression vector encoding chimeric antigen receptor scFv anti-erbB2-CD28-ζ and to investigate the expression and action of this chimeric antigen receptor in cancer cells both in vitro and in vivo, NK-92 cells were genetically modified with an scFv anti-erbB2-CD28-ζ chimeric recep tor by optimized electro poration using the Amaxa Nucleofector system. The expression of the chimeric receptor was evaluated by RT-PCR and immunofluorescence. The ability of the genetically modified NK-92 cells to induce cell death in tumor targets was assessed in vitro and in vivo. The transduced NK-92-anti-erbB2 scFv-CD28-ζ cells expressing high levels of the fusion protein on the cell surface were analyzed by fluorescence-activated cell-sorting (FACS) analysis. These cells specifically enhanced the cell death of the erbB2-expressing human breast cancer cell lines MDA-MB-453 and SKBr3. Furthermore, adoptive transfer of genetically modified NK-92 cells specifically reduced tumor size and lung metastasis of nude mice bearing established MDA-MB-453 cells, and significantly enhanced the survival period of these mice. The genetically modified NK-92 cells significantly enhanced the killing of erbB2-expressing cancer and may be a novel therapeutic strategy for erbB2-expressing cancer cells.

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Section: Discussionmentioning

confidence: 99%

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Liu

Yang

Sun³

et al. 2014

Oncol Rep

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“…However, the use of human erbB2 ϩ transgenic mice may serve as a better model to evaluate potential autoimmunity from transferred gene-modified NK cells. This model will also enable us to assess the effect of self-Ag on anti-tumor immunity following NK cell transfer (47). In any case, if autoimmune problems were to arise, the incorporation of a suicide gene in the vector design could be used to eliminate these gene-modified NK cells.…”

Section: Discussionmentioning

confidence: 99%

Adoptive Transfer of Gene-Modified Primary NK Cells Can Specifically Inhibit Tumor Progression In Vivo

Pegram

Jackson

Smyth

et al. 2008

The Journal of Immunology

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NK cells hold great potential for improving the immunotherapy of cancer. Nevertheless, tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2 tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti-erbB2 Ab linked to the transmembrane and cytoplasmic CD28 and TCR-ζ signaling domains (scFv-CD28-ζ). In this study we demonstrated that mouse NK cells gene-modified with this chimera could specifically mediate enhanced killing of an erbB2+ MHC class I+ lymphoma in a perforin-dependent manner. Expression of the chimera did not interfere with NK cell-mediated cytotoxicity mediated by endogenous NK receptors. Furthermore, adoptive transfer of gene-modified NK cells significantly enhanced the survival of RAG mice bearing established i.p. RMA-erbB2+ lymphoma. In summary, these data suggest that use of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients.

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“…This indicates that cross-reactive immune responses are possible, and suggests that at least for this particular epitope tolerance to endogenous murine ErbB2 might have to be overcome to mount an effective response against the human peptide. Subsequent studies in animals such as the recently described ErbB2/HER2 transgenic mice (Piechocki et al, 2003) will help to further investigate the potential of liposomal ErbB2 vaccines to break endogenous tolerance against this antigen.…”

Section: Discussionmentioning

confidence: 99%

Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

et al. 2005

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Efficient delivery of tumour-associated antigens to appropriate cellular compartments of antigen-presenting cells is of prime importance for the induction of potent, cell-mediated antitumour immune responses. We have designed novel multivalent liposomal constructs that co-deliver the p63 -71 cytotoxic T Lymphocyte epitope derived from human ErbB2 (HER2), and HA307 -319, a T-helper (Th) epitope derived from influenza haemagglutinin. Both peptides were conjugated to the surface of liposomes via a Pam 3 CSS anchor, a synthetic lipopeptide with potent adjuvant activity. In a murine model system, vaccination with these constructs completely protected BALB/c mice from subsequent s.c. challenge with ErbB2-expressing, but not ErbB2-negative, murine renal carcinoma (Renca) cells, indicating the induction of potent, antigen-specific immune responses. I.v. re-challenge of tumour-free animals 2 months after the first tumour cell inoculation did not result in the formation of lung tumour nodules, suggesting that longlasting, systemic immunity had been induced. While still protecting the majority of vaccinated mice, a liposomal construct lacking the Th epitope was less effective than the diepitope construct, also correlating with a lower number of CD8 þ IFN-g þ T-cells identified upon ex vivo peptide restimulation of splenocytes from vaccinated animals. Importantly, in a therapeutic setting treatment with the liposomal vaccines resulted in cures in the majority of tumour-bearing mice and delayed tumour growth in the remaining ones. Our results demonstrate that liposomal constructs which combine Tc and Th peptide antigens and lipopeptide adjuvants can induce efficient, antigen-specific antitumour immunity, and represent promising synthetic delivery systems for the design of specific antitumour vaccines.

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Human ErbB-2 (Her-2) Transgenic Mice: A Model System for Testing Her-2 Based Vaccines

Cited by 109 publications

References 27 publications

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

Adoptive Transfer of Gene-Modified Primary NK Cells Can Specifically Inhibit Tumor Progression In Vivo

Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

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