title: Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Ospedale San Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Spadaro
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrosino
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.forename: Pamela
authors.initials: P
authors.lastname: Sacchetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Curcio
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
authors.forename: Piero
authors.initials: P
authors.lastname: Musiani
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.forename: Guido
authors.initials: G
authors.lastname: Forni
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology*; D018274:Electroporation; D005260:Female; D018734:Genes, erbB-2; D007107:Immune System / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020360:Neoadjuvant Therapy; D010957:Plasmids / Q000235:genetics
chemical_list: D019496:Cancer Vaccines; D018664:Interleukin-12