Polyethylenimine-mediated in vivo gene transfer of a transmembrane superantigen fusion construct inhibits B16 murine melanoma growth.
Immunotherapy has been proposed as a therapeutic strategy in advanced-stage melanomas in which other therapeutic options have little effect. The Staphylococcus enterotoxin A (SEA) has been used to stimulate an antitumoral immune response but its use is hampered by severe systemic side effects. Here, we show that SEA can be targeted to melanoma cells to limit these side effects. More specifically, we used a nonviral vector, the cationic polymer, polyethylenimine (PEI), to express a transmembrane SEA fusion construct (pSEA-TM) in B16F10-induced subcutaneous melanoma in mice. The efficacy of this in vivo transfection was enhanced by concomitant infusion of epinephrine to induce local vasoconstriction. In these conditions, repeated injections of pSEA-TM/PEI complexes elicited a significant response, as evidenced by tumor growth inhibition, without systemic adverse effects. T cell infiltration of the tumors, together with positive lymphocyte proliferation tests, suggested local and systemic immune responses. Altogether, PEI-mediated targeting of SEA to melanoma tumor cells in vivo efficiently stimulates the antitumor immune response without inducing the side effects observed with systemic administration of SEA.
Jeudy
G
G
Inserm U866, IFR100, Faculté de Médecine, Dijon, France.
Salvadori
F
F
Chauffert
B
B
Solary
E
E
Vabres
P
P
Chluba
J
J
D000818:Animals; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004837:Epinephrine; D019084:Fluorescent Antibody Technique, Indirect; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008856:Microscopy, Fluorescence; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011094:Polyethyleneimine / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013211:Staphylococcus aureus; D018709:Statistics, Nonparametric; D018089:Superantigens / Q000235:genetics / Q000276:immunology*
D017931:DNA Primers; D004768:Enterotoxins; D015514:Oncogene Proteins, Fusion; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; D011094:Polyethyleneimine; D004837:Epinephrine