9th Latin American Congress of 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 Immunology (ALAI)-XII Chilean Society of Immunology Congress; 2009

Sociedad Latinoamericana y Sociedad Chilena de Inmunologia

IL-12 is an excellent candidate for the treatment of cancer due to its ability to drive strong anti-tumor responses. Recombinant IL-12 (rIL-12) protein is currently being tested in cancer patients, however, systemic expression of rIL-12 presents several disadvantages including cost and dose limitation due to possible toxicity. In this study we focused on strategies for attenuating systemic IL-12 toxicity without affecting its anti-tumor properties. Using hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12, we found that sustained but toxic levels of IL-12 could be generated in the sera of mice. Unexpectedly, we observed that when IL-12 cDNA was co-injected with IL-18 cDNA, the anti-tumor activity of the IL-12 was maintained but there was a significant attenuation of IL-12 toxicity, as evidenced by a greater survival index, diminution of liver enzymes (ALT and AST) and reduced inflammatory infiltrate in several organs. Moreover, after IL-12+IL-18 expression, IL-10 was  expressed much earlier than when IL-12 cDNA was given alone. To understand the mechanism of protection, we co-injected IL-12+IL-10 cDNA and observed an increase in survival that correlated with diminished sera levels of inflammatory cytokines, including TNFa and IFNg. Confirming the protective role of early IL-10 expression, we observed that when IL-10R was blocked in IL-12+IL-18 mice at the time of cDNA injection, 100% of mice died. Thus, our data demonstrate that the timing of IL-10 expression contributes to attenuate IL-12 toxicity and could improve the design of less toxic protocols for the treatment of cancer patients.