This project investigates the ability of recombinant vaccinia and herpes virus vectors to serve as delivery vehicles for immunomodulatory cytokines. Studies to date have focused on the ability of recombinant vaccinia virus expressing murine Interleukin 4 (VV1/IL4) to modulate the course of tumor development in experimental animals (inbred mice). When mice were treated once with a subcutaneous (sc) inoculation of VV1/IL4 at a site adjacent to sc inoculation of tumor cells, tumor growth was significantly delayed. More importantly, repeated weekly treatment with VV1/IL4 at the site of tumor cell inoculation completely ablated subsequent tumor formation. This modulation of tumor growth was dependent on the dose of virus used for treatment. It was further dependent on the presence of mature T lymphocytes in the host, since repeated treatment of athymic nu/nu mice with VV1/IL4 had no effect on tumor development. Interestingly, treatment with a control recombinant virus that expressed only a marker gene, beta- galactosidase (VV2/betagal), also delayed or prevented sc tumor development in up to 40% of mice. Results to date suggest that nonspecific activation of macrophages and tumor necrosis factor production by vaccinia virus infection is responsible for some of the anti-tumor effects. These nonspecific effects may synergize with IL4-mediated activation of host tumor specific T cells to effect complete control of tumor development. Further, sc inoculation of vaccinia virus results in significant virus infection and replication in the skin, but much less in other major organs; this suggests that recombinant vaccinia viruses may be especially well suited for delivery of immunomodulatory cytokines to skin-related tumors.
