HER2/neu DNA vaccination by intradermal gene delivery in a mouse tumor model

DNA vaccines are potential tools for the induction of immune responses against both infectious disease and cancer. The dermal application of DNA vaccines is of particular interest since the epidermal and dermal layers of the skin are characterized by an abundance of antigen-presenting cells (APCs). The aim of our study was to compare tumor protection as obtained by two different methods of intradermal DNA delivery (gene gun and jet injector) in a well-established HER2/neu mouse tumor model. BALB/c mice were immunized twice with a HER2/neu-coding plasmid by gene gun or jet injector. Mice were then subcutaneously challenged with HER2/neu+ syngeneic D2F2/E2 tumor cells. Protection against subsequent challenges with tumor cells as well as humoral and T-cell immune responses induced by the vaccine were monitored. Gene gun immunization was far superior to jet injector both in terms of tumor protection and induction of HER2/neu-specific immune responses. After gene gun immunization, 60% of the mice remained tumor-free until day 140 as compared with 25% after jet injector immunization. Furthermore, gene gun vaccination was able to induce both a strong TH1-polarized T-cell response with detectable cytotoxic T-lymphocyte (CTL) activity and a humoral immune response against HER2/neu, whereas the jet injector was not. Although the disadvantages that were associated with the use of the jet injector in our model may be overcome with methodological modifications and/or in larger animals, which exhibit a thicker skin and/or subcutaneous muscle tissue, we conclude that gene gun delivery constitutes the method of choice for intradermal DNA delivery in preclinical mouse models and possibly also for the clinical development of DNA-based vaccines.

[1]  B. Dörken,et al.  CCL19 (ELC) improves TH1‐polarized immune responses and protective immunity in a murine Her2/neu DNA vaccination model , 2012, The journal of gene medicine.

[2]  M. Levine,et al.  Safety, tolerability, and immunogenicity of inactivated trivalent seasonal influenza vaccine administered with a needle-free disposable-syringe jet injector. , 2011, Vaccine.

[3]  B. Dörken,et al.  CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model , 2011, Cancer Gene Therapy.

[4]  D. Weiner,et al.  Selected approaches for increasing HIV DNA vaccine immunogenicity in vivo. , 2011, Current opinion in virology.

[5]  N. Sardesai,et al.  A novel prototype device for electroporation-enhanced DNA vaccine delivery simultaneously to both skin and muscle. , 2011, Vaccine.

[6]  C. Bode,et al.  TLR-based immune adjuvants. , 2011, Vaccine.

[7]  L. Zitvogel,et al.  The dendritic cell-tumor cross-talk in cancer. , 2011, Current opinion in immunology.

[8]  B. Malissen,et al.  Langerin+ Dermal Dendritic Cells Are Critical for CD8+ T Cell Activation and IgH γ-1 Class Switching in Response to Gene Gun Vaccines , 2011, The Journal of Immunology.

[9]  M. Sällberg,et al.  Electroporation: a promising method for the nonviral delivery of DNA vaccines in humans? , 2010, Drug news & perspectives.

[10]  H. Okada,et al.  Local gene expression and immune responses of vaginal DNA vaccination using a needle-free injector. , 2010, International journal of pharmaceutics.

[11]  D. Speiser,et al.  Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity. , 2010, Seminars in immunology.

[12]  S. Perez,et al.  HER-2/neu as a target for cancer vaccines. , 2010, Immunotherapy.

[13]  Peter M. Schlag,et al.  Novel Jet-Injection Technology for Nonviral Intratumoral Gene Transfer in Patients with Melanoma and Breast Cancer , 2008, Clinical Cancer Research.

[14]  C. Ottensmeier,et al.  DNA vaccines: precision tools for activating effective immunity against cancer , 2008, Nature Reviews Cancer.

[15]  E. Mittendorf,et al.  Combined Clinical Trial Results of a HER2/neu (E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02 , 2008, Clinical Cancer Research.

[16]  B. Malissen,et al.  Epidermal Langerhans Cells Are Dispensable for Humoral and Cell-Mediated Immunity Elicited by Gene Gun Immunization1 , 2007, The Journal of Immunology.

[17]  N. Letvin,et al.  Chemical adjuvants for plasmid DNA vaccines. , 2007, Vaccine.

[18]  Samir Mitragotri,et al.  Current status and future prospects of needle-free liquid jet injectors , 2006, Nature Reviews Drug Discovery.

[19]  A. Goldhirsch,et al.  Breast cancer vaccines: a clinical reality or fairy tale? , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  M. Provinciali,et al.  Evaluation of different plasmid DNA delivery systems for immunization against HER2/neu in a transgenic murine model of mammary carcinoma. , 2006, Vaccine.

[21]  P. Schlag,et al.  Nonviral jet-injection gene transfer for efficient in vivo cytosine deaminase suicide gene therapy of colon carcinoma. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  Chien-Fu Hung,et al.  A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression , 2005, Nature Medicine.

[23]  E. Konishi,et al.  Needle-free jet injection of a mixture of Japanese encephalitis DNA and protein vaccines: a strategy to effectively enhance immunogenicity of the DNA vaccine in a murine model. , 2005, Viral immunology.

[24]  M. Moser,et al.  Consensual immunity: success-driven development of T-helper-1 and T-helper-2 responses , 2005, Nature Reviews Immunology.

[25]  G. Prud’homme.  DNA vaccination against tumors , 2005, The journal of gene medicine.

[26]  D. Weiner,et al.  Developing DNA vaccines that call to dendritic cells. , 2004, The Journal of clinical investigation.

[27]  H. Ikeda,et al.  The critical role of type‐1 innate and acquired immunity in tumor immunotherapy , 2004, Cancer science.

[28]  Samir Mitragotri,et al.  Needle-free jet injections: dependence of jet penetration and dispersion in the skin on jet power. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[29]  B. Seliger,et al.  CD4+ T cell‐mediated HER‐2/neu‐specific tumor rejection in the absence of B cells , 2004, International journal of cancer.

[30]  O. Janoušková,et al.  Delivery of recombinant adeno-associated virus by jet injection. , 2003, International journal of molecular medicine.

[31]  M. Campiglio,et al.  Biologic and therapeutic role of HER2 in cancer , 2003, Oncogene.

[32]  D. Pardoll,et al.  Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe. , 2003, Vaccine.

[33]  N. Romani,et al.  Langerhans cells – dendritic cells of the epidermis , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[34]  M. Moser.  Dendritic cells in immunity and tolerance-do they display opposite functions? , 2003, Immunity.

[35]  Piero Musiani,et al.  Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her-2/neu carcinomas. , 2003, The Journal of clinical investigation.

[36]  L. Babiuk,et al.  Induction of immune responses by DNA vaccines in large animals. , 2003, Vaccine.

[37]  P. Furth,et al.  Low-volume jet injection for intradermal immunization in rabbits , 2002, BMC biotechnology.

[38]  J. Y. Scheerlinck,et al.  Genetic adjuvants for DNA vaccines. , 2001, Vaccine.

[39]  G. Schuler,et al.  A strikingly constant ratio exists between Langerhans cells and other epidermal cells in human skin. A stereologic study using the optical disector method and the confocal laser scanning microscope. , 2001, The Journal of investigative dermatology.

[40]  R. Schreiber,et al.  Eradication of established tumors by CD8+ T cell adoptive immunotherapy. , 2000, Immunity.

[41]  K. Tamai,et al.  In vivo gene introduction into keratinocytes using jet injection , 1999, Gene Therapy.

[42]  Y. Girerd-Chambaz,et al.  Intradermal DNA immunization by using jet-injectors in mice and monkeys. , 1999, Vaccine.

[43]  R. Germain,et al.  Predominant Role for Directly Transfected Dendritic Cells in Antigen Presentation to CD8+ T Cells after Gene Gun Immunization , 1998, The Journal of experimental medicine.

[44]  R. Webster,et al.  Induction of CD8+ T cell responses to dominant and subdominant epitopes and protective immunity to Sendai virus infection by DNA vaccination. , 1998, Journal of immunology.

[45]  H. Ikeda,et al.  Peptides derived from a wild-type murine proto-oncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts. , 1997, Journal of immunology.

[46]  Simon C Watkins,et al.  DNA–based immunization by in vivo transfection of dendritic cells , 1996, Nature Medicine.

[47]  M. Manthorpe,et al.  Immunization with plasmid DNA using a pneumatic gun. , 1994, Journal of immunological methods.

[48]  G. Schuler,et al.  Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. , 1993, The Journal of clinical investigation.

[49]  G. Acsadi,et al.  Direct gene transfer into mouse muscle in vivo. , 1990, Science.

[50]  P. Greenberg,et al.  Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes , 1981, The Journal of experimental medicine.

[51]  J. Streilein,et al.  Surface densities of Langerhans cells in relation to rodent epidermal sites with special immunologic properties. , 1980, The Journal of investigative dermatology.

[52]  W. Walther,et al.  Jet-injection of short hairpin RNA-encoding vectors into tumor cells. , 2010, Methods in molecular biology.

[53]  S. H. van der Burg,et al.  Vaccination for treatment and prevention of cancer in animal models. , 2006, Advances in immunology.

[54]  Kanakatte Raviprakash,et al.  Needle-free injection of DNA vaccines: a brief overview and methodology. , 2006, Methods in molecular medicine.

[55]  J. Kim,et al.  DNA vaccination in immunotherapy of cancer. , 2005, Cancer treatment and research.

[56]  P. Schlag,et al.  Low-volume jet injection for efficient nonviral in vivo gene transfer , 2004, Molecular biotechnology.

[57]  M. Piechocki,et al.  Quantitative measurement of anti-ErbB-2 antibody by flow cytometry and ELISA. , 2002, Journal of immunological methods.

[58]  I. Fichtner,et al.  Nonviral in vivo gene delivery into tumors using a novel low volume jet-injection technology , 2001, Gene Therapy.

[59]  S. Gurunathan,et al.  DNA vaccines: immunology, application, and optimization*. , 2000, Annual review of immunology.