Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12

The antitumor immune response activated by IL-12, especially by a combinati on of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in c ertain experimental tumor models, in that a number of well-established (10- 20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+I L-12 treatment is also able to eradicate well-established grossly detectabl e experimental lung metastases and advanced ascites tumors. Despite the dra matic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunoge nicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments ar e immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the non immunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of ce llular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not n aive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Trans fer of these tumor-sensitized T cells must be conducted before, but not aft er, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic t umors, the presence of pre-existing tumor-sensitized T cells is demonstrate d by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy o f cancer may be highly effective and that pre-existing tumor-sensitized T c ells are essential for the success of the therapy.