Tumor regression induced by intratumor administration of adenovirus vectorexpressing CD40 ligand and naive dendritic cells

We have previously shown that in vivo genetic modification of tumors with a n adenovirus (Ad) vector engineered to express CD40 ligand (AdmCD40L) induc es tumor-specific CTLs and suppresses tumor growth in vivo. In the present study, we investigate the hypothesis that this treatment can be made more e fficient with 10(2)-fold less Ad vector by also administering bone marrow-g enerated dendritic cells (DCs) to the tumor. Using AdmCD40L and the number of DCs that alone had no effect on tumor growth, the data show that the gro wth of CT26 (colon adenocarcinoma; H-2(d)) and B16 (melanoma; H-2(b)) murin e s,c, tumors is significantly suppressed by direct administration of DCs i nto s,c, established tumors that had been pretreated with AdmCD40L 2 days p reviously. The antitumor effect produced by the combination therapy of AdmC D40L + DCs correlated with in vivo priming of tumor-specific CTLs, The anti tumor cell-mediated immunity was transferable to naive mice by spleen cells from AdmCD40L + DC-treated animals. The interactions between CD40L and CD4 0 within treated tumors were critical because tumor suppression was abrogat ed by coadministration to the tumors of neutralizing monoclonal antibody ag ainst CD40L along with the DCs. Finally, in vivo depletion and knockout mic e experiments demonstrated that tumor regression produced by this combinati on therapy depends on CD8+ T cells, but not on CD4+ T cells. These findings should be useful in designing strategies for use of DCs and AdmCD40L in ca ncer immunotherapy.