Cancer Immunotherapy: Consequences of the use of IL-12 and IL-18 cDNA expression vectors for cancer therapy

RODRIGUEZ-GALAN MC, REYNOLDS D, WATANABE M, IRIBARREN P, CORREA SG, RIERA CM, YOUNG HA.

Rio de Janeiro

Congreso; XIII International Congress of Immunology and VIII Latin American Congress of Immunology (ALAI).; 2007

IUIS y ALAI

  IL-12 is a cytokine currently used in clinical trials in cancer patients. A major disadvantage of this treatment is cost, toxicity and dose limitation. The aim of our study was to find an alternative way to deliver/express IL-12 maintaining its excellent anti-tumoral properties but diminishing its toxic side effects. Here we report that elevated and sustained levels of IL-12 can be expressed in the sera of mice upon a single hydrodynamic injection of the cDNA. Interestingly, the considerably toxicity observed in young C57BL/6 mice is not observed in mice older than 10 weeks or in BALB/c mice. Moreover, co-expression of IL-12 and IL-18 significantly attenuates IL-12-toxicity as measured by the survival index, diminution in the liver function enzymes and reduced inflammatory infiltrate in several vital organs. The injection of IL-12 or IL-12+IL-18 cDNAs had significant beneficial effects as mice were able to eliminate almost all B16 or 3LL liver metastases or subcutaneous growth of B16 melanoma cells. The toxic effects that occur after IL-12 expression did not correlate with nitric oxide production or the presence of NK cells as iNOS KO mice or NK1.1-Ab depleted animals showed similar survival index than control mice. However, IL-12-mediated toxicity is substantially attenuated in RAG -/- mice or after simultaneous depletion of CD4+ and CD8+ T cells in normal mice. The present data demonstrate the benefit of using IL-12 and IL-18 cDNA expression as a powerful tool with minimal toxicity in cancer therapy.