Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation

In an orthotopic model of metastatic colon carcinoma established in the liv er of mice, we have previously shown that the natural killer (NK) cells wer e the major effecters after intratumoral delivery of a recombinant adenovir us expressing the murine IL-12 gene. However, tumor cure and long-term surv ival were achieved only in a minority of animals. In the present study, we generated an effective antitumoral CD8(+) T-cell response by the combinatio n of IL-12 gene therapy and systemic delivery of an agonistic monoclonal an tibody against 4-1BB, a costimulatory molecule expressed on activated T cel ls. In the IL-12 plus anti-4-1BB combination treatment, the effective dose of IL-12 could even be reduced even up to 18-fold and still achieved a bett er efficacy than the maximal dose of either treatment alone. We further dem onstrate that the innate and the adaptive antitumoral immune responses were synergistic, as animals bearing hepatic as well as multiple pulmonary meta stases were quantitatively cured of their diseases after IL-12 gene therapy + anti-4-1BB combination treatment. Both NK and CD8(+) T cells were necess ary in maintaining the long-term antitumor immunity, as depletion of either cell type in the cured animals abolished their abilities to reject tumor c ells implanted at distal sites. These results indicate that synergism betwe en innate and adaptive immune responses may be effectively exploited to tre at patients with metastatic diseases.