Immunotherapy for murine K1735 melanoma: Combinatorial use of recombinant adenovirus expressing CD40L and other immunomodulators

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Abstract
We have constructed and tested five recombinant adenoviruses (Ads) that express a variety of immunomodulators, including CD40 ligand (CD40L), a potent costimulator of several components of the immune system. We demonstrate that CD40L expressed from Ad in K1735 mouse melanoma cells leads to a strong reduction in tumorigenicity and to efficient protective immunity in a vaccination setting. Subsequently, using a therapeutic approach, we found that local, intratumoral coinjection of CD40L- and IL-2–expressing Ads was superior to any other agents tested and resulted in an at least 1.9-fold increase in mean survival time, in contrast to systemic application of recombinant CD40L or GM-CSF proteins, which had no significant effects. When using vaccination as a therapeutic approach, the combinations of CD40L plus IL-2 or GM-CSF plus IL-2 from Ad gave rise to an extended (2.8-fold) increase in mean survival time. A detailed analysis of immune cells present within regressing tumors indicated that mainly CD4+ and CD8+ T cells, and to a lesser extent dendritic cells, infiltrated the tumor mass, but not NK cells, macrophages, or granulocytes. These results propose that a combination of CD40L plus IL-2 has an improved efficacy over the use of single agents when applied for direct in situ therapy or vaccination therapy.