Attenuation of Interleukin-12 (IL-12) systemic toxicity by IL-18 in gene therapy in a B16 melanoma murine model: Role of endogenous IL-10 production

RODRÍGUEZ GALÁN MC; CORREA SG.; REYNOLDS D; YOUNG HA

Viña del Mar, Chile.

Congreso; 9th Latin American Congress of Imunology (ALAI).; 2009

Asociación Latinoamericana de Inmunología (ALAI)

Recombinant IL-12 protein is currently used as treatment in cancer patients; however, its systemic expression still presents high toxicity. Here, we used hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12. We found sustained but toxic levels of serum IL-12 in 6-7 week old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that co-injection of IL-12+IL-18 cDNAs presented similar anti-tumor activity with a significant attenuation in IL-12 toxicity evaluated by morbidity and survival of the mice. Toxicity seems to be induced by IFNg and TNFa. Interestingly, after IL-12+IL-18 expression, serum IL-10 levels were faster and higher than after IL-12 cDNA treatment possibly controlling IFNg and TNFa serum levels. Analysis of sorted spleen cells subsets from IL-12+IL-18 mice demonstrate that the main producers of these cytokines are CD8+ and CD11b/c+ cells for TNFa, CD4+ and CD8+ cells for IFNg and CD4+ and CD11b/c+ cells for IL-10. Together, early IL-10 expression induced after IL-12+IL-18 cDNA treatment is critical to rapidly attenuate IL-12 toxicity without affecting its anti-tumor capacity. These data could contribute to the design of less toxic/more efficient protocols for the treatment of cancer.