Immunotherapy for lung metastases of murine renal cell carcinoma: Synergy between radiation and cytokine-producing tumor vaccines

We investigated the combination therapy of local radiation of lung metastas is and vaccination with autologous tumor cells that produced interleukin (I L)-2, interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimu lating factor (GM-CSF) using the mouse Renca pulmonary metastasis model. Wi ld-type Renca (W/Renca) were transfected with pEF-BOS vector incorporating cDNAs for IL-2, IFN-gamma, or GM-CSF to express these cytokines. W/Renca, I L-2-producing Renca (Renca/IL-2), and IFN-gamma-producing Renca (Renca/IFN- gamma) produced subcutaneous tumor at the injection site in eight of eight, one of eight, and two of eight mice, respectively. No tumors were found in the GM-CSF-produced Renca (Renca/GM-CSF) group (zero of eight). Renca/IFN- gamma produced subcutaneous (s.c.) tumors in all Balb/c nude mice, but Renc a/IL-2 and Renca/GM-CSF did not. To test the elicitation of antitumor activ ity, Balb/c mice were injected intravenously with 1 x 10 W/Renca on day 0, vaccinated, s.c., with 1 x 10(6) cells each of 5,000 rad preirradiated Renc a/IL-2, Renca/IFN-gamma, and Renca/GM-CSF or 3 x 10(6) cells of preirradiat ed W/Renca on days 1, 7, and 14, and radiated with 300 rad to both lungs on day 5. The animals were killed on day 21 and tumor nodules in the lungs we re enumerated. Neither local irradiation alone nor the combination of lung radiation and multiple vaccination with irradiated W/Renca significantly re duced the number of lung tumors. In contrast, the combination of lung radia tion and the multiple vaccinations with cytokine-producing Renca cells sign ificantly reduced the number of lung tumors. This regimen was more effectiv e than the multiple vaccinations with cytokine-producing Renca cells alone. These studies demonstrate the efficacy of vaccination with autologous tumo r cells expressing these cytokines and sensitization of the tumor target wi th radiation.