Complete tumour regressions induced by vaccination with IL-12 gene-transduced tumour cells in combination with IL-15 in a melanoma model in mice.
In the present study, IL-12 gene-transduced B78-H1 melanoma cells (B78/IL-12) were used in combination with IL-15 to treat melanoma-bearing mice. Genetically modified B78/IL-12 cells, when injected subcutaneously, induced strong activation of antitumour mechanisms resulting in complete loss of tumourigenicity. In a therapeutic model, intratumoural injection of irradiated B78/IL-12 cells significantly delayed tumour growth and led to the regression of melanoma in one case. Similarly, consecutive daily injections of IL-15 markedly inhibited tumour progression with occasional curative effects. When used in combination, vaccination with B78/IL-12 cells and treatment with IL-15 caused eradication of established tumours in all treated mice. The combined treatment with B78/IL-12 cells and IL-15 activated not only a local response against tumour, but also induced systemic antitumour immunity that led to a delay or inhibition of tumour development at a distant site. In vitro studies demonstrated that when used together, B78/IL-12 cells and IL-15 induced a shift from a type Th2 to a type Th1 response. Activation of the antitumour immune response in double-treated mice resulted, in part, from stimulation of IFN-gamma production and was accompanied by the development of cytotoxic effectors in the spleen. As shown in a macrophage tumouricidal assay, macrophages could also play a role in the antitumour effects. The results confirmed that vaccination with IL-12 gene-modified tumour cells is superior to the treatment with unmodified tumour cell vaccine and, additionally, showed that IL-15 is an excellent candidate for adjuvant therapy, inducing synergistically not only a delay of tumour growth but also its complete eradication.
Lasek
Witold
W
Department of Immunology, Centre of Biostructure, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland. wlasek@ib.amwaw.edu.pl
Basak
Grzegorz
G
Switaj
Tomasz
T
Jakubowska
Anna B
AB
Wysocki
Piotr J
PJ
Mackiewicz
Andrzej
A
Drela
Nadzieja
N
Jalili
Ahmad
A
Kamiński
Rafał
R
Kozar
Katarzyna
K
Jakóbisiak
Marek
M
D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics*; D019409:Interleukin-15 / Q000235:genetics*; D008198:Lymph Nodes / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014611:Vaccination
D019409:Interleukin-15; D018664:Interleukin-12; D007371:Interferon-gamma