Antitumor Effect of Interferon Plus Cyclosporine A Following Chemotherapy for Disseminated Melanoma

Interferon (IFN) increases the expression of major histocompatibility (MHC) antigens on the surface of tumor cells. Cyclosporine A (CsA) administration following myeloablative therapy and syngeneic bone marrow transplantation results in the generation of cells with autoreactive and antitumor effects that are related to the expression of MHC antigens. We used these two agents following conventional chemotherapy in a non-bone marrow transplantation setting for a melanoma in a murine model. Treatment with IFN alone or CsA alone was ineffective in controlling the dissemination of melanoma. A combination therapy with both these agents resulted in a significant control in the dissemination of the tumor, prolonged the survival of the tumor-bearing mice over that with chemotherapy alone, and generated cells with potent MHC-unrestricted cytotoxic potential in vitro. Adoptive transfer of these cells to secondary tumor bearers treated with chemotherapy showed potent antitumor effect; in the absence of chemotherapy, these cells had no antitumor effect in the secondary recipients. The antitumor effect of cells generated by IFN plus CsA therapy following chemotherapy could be blocked by normal spleen cells. These data suggest that treatment with IFN plus CsA following nonmyeloablative chemotherapy generates cells with MHC-unrestricted cytotoxicity; this effect may be related to abolition of suppressor influences by the chemotherapy.