Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level

Tumors infected with a recombinant defective adenovirus expressing interleu kin 12 (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)-mediated antitumor immune response, In the present study we generate d anti-CT26 CTLs by short-term coculture of CT26 cells and lymph node cells obtained from mice harboring subcutaneous CT26 tumors injected with an ade noviral vector expressing IL-12 (Ad-CMVIL-12), control adenovirus (AdCMVlac Z), or saline, Regression of small intrahepatic CT26 tumors in unrelated sy ngeneic animals was achieved with CTLs derived from mice whose subcutaneous tumors had been injected with AdCMVIL-12 but not with CTLs from the other two control groups, The necessary and sufficient effector cell population f or adoptive transfer consisted of CD8(+) T cells that showed anti-CT26 spec ificity partly directed against the AH1 epitope presented by H-2L(d), Inter estingly, treatment of a subcutaneous tumor nodule with AdCMVIL-12, combine d with intravenous adoptive T cell therapy with short-term CTL cultures, ha d a marked synergistic effect against large, concomitant live tumors. Expre ssion of IL-12 in the liver in the vicinity of the hepatic tumor nodules, o wing to spillover of the vector into the systemic circulation, appeared to be involved in the increased in vivo antitumor activity of injected CTLs, I n addition, adoptive T cell therapy improved the outcome of tumor nodules t ransduced with suboptimal doses of AdCMVIL-12, Our data provide evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell therap y, This synergy operates both at the induction and effector phases of the C TL response, thus providing a rationale for combined therapeutic strategies for human malignancies.