A multi-DNA preventive vaccine for p53/Neu-driven cancer syndrome.
The highly aggressive cancer syndrome of female mice carrying a p53 knockout allele and a rat HER-2/neu (Neu) transgene (BALB-p53Neu) can be prevented by a cell vaccine presenting three components: Neu, interleukin (IL)-12 production, and allogeneic major histocompatibility complex (MHC) alleles (Triplex cell vaccine). Here we tested a second-generation Triplex DNA-based vaccine (Tri-DNA), consisting of the combination of three gene components (a transmembrane-extracellular domain fragment of the Neu gene, IL-12 genes, and the H-2D(q) allogeneic MHC gene), carried by separate plasmids. The Tri-DNA vaccine was at least as effective as the Triplex cell vaccine for cancer immunoprevention, giving a similar delay in the onset of mammary cancer and complete protection from salivary cancer. Both vaccines induced anti-Neu antibodies of the murine IgG2a isotype at similar levels. The Tri-DNA vaccine gave more restricted immunostimulation, consisting of a fully helper T cell type 1 (Th1)-polarized response, with effective production of interferon (IFN)-gamma in response to the vaccine but no spontaneous production, and no induction of anti-Neu IgG3 antibodies. On the other hand, the Triplex cell vaccine induced both Th1 and Th2 cytokines, a strong increase in spontaneous IFN-gamma production, and high levels of IgG3 antibodies recognizing Neu-positive syngeneic cells. In conclusion, the Tri-DNA vaccine is as effective as Triplex cell vaccine, exploiting a more restricted immune stimulation.
De Giovanni
C
C
Cancer Research Section, Department of Experimental Pathology, Alma Mater Studiorum, University of Bologna, I-40126 Bologna, Italy. carla.degiovanni@unibo.it
Nicoletti
G
G
Palladini
A
A
Croci
S
S
Landuzzi
L
L
Antognoli
A
A
Murgo
A
A
Astolfi
A
A
Ferrini
S
S
Fabbi
M
M
Orengo
A M
AM
Amici
A
A
Penichet
M L
ML
Aurisicchio
L
L
Iezzi
M
M
Musiani
P
P
Nanni
P
P
Lollini
P-L
PL
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D015316:Genetic Therapy; D007074:Immunoglobulin G / Q000097:blood; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D008321:Mammary Glands, Animal / Q000276:immunology / Q000473:pathology; D051379:Mice; D009386:Neoplastic Syndromes, Hereditary / Q000517:prevention & control* / Q000628:therapy; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000276:immunology*
D019496:Cancer Vaccines; D016207:Cytokines; D007074:Immunoglobulin G; D007371:Interferon-gamma; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D019444:Vaccines, DNA