Genetic heterogeneity in the toxicity to systemic adenoviral gene transferof interleukin-12

Despite the efficacy of IL-12 in cancer experimental models, clinical trial s with systemic recombinant IL-12 showed unacceptable toxicity related to e ndogenous IFN gamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically dif ferent survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFN gamma concentr ations in serum samples of C57BL/6 than in those from identically treated B ALB/c were found Causes for heterogeneous toxicity can be traced to differe nces among murine strains in the levels of gene transduction achieved in th e liver, as assessed with adenovirus coding for reporter genes. In accordan ce, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL -18, a well-known IFN gamma inducer. Interestingly, lethal toxicity in C57B L/6 mice was abolished by administration of blocking anti-IFN gamma mAbs an d also by simultaneous depletion of T cells, NK cells, and macrophages. The se observations together with the great dispersion of IFN gamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recomb inant adenovirus encoding IL-12, suggest that patients might also show hete rogeneous degrees of toxicity in response to IL-12 gene transfer.