Immunotherapy with vaccines combining MHC class II/CD80(+) tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon gamma

Because they are difficult to treat, animal models of widespread, establish ed metastatic cancer are rarely used to test novel immunotherapies. Two suc h mouse models are used in this report to demonstrate the therapeutic effic acy and to probe the mechanisms of a novel combination irnmunotherapy consi sting of the cytokine interleukin-12 (IL-12) combined with a previously des cribed vaccine based on MHC class II, CD80-expressing cells. BALB/c mice wi th 3-week established primary 4T1 mammary carcinomas up to 6 mm in diameter and with extensive, spontaneous lung metastases show a significant reducti on in lung metastases following a 3-week course of immunotherapy consisting of weekly injections of the cell-based vaccine plus injections of IL-12 th ree Limes per week. C57BL/6 mice with 7-day established intravenous B16 mel F10 lung metastases show a similar response following immunotherapy with IL -12 plus a vaccine based on B16 MHC class II, CD80-expressing cells. In bot h systems the combination therapy of cells plus IL-12 is more effective tha n IL-12 or the cellular vaccine alone, although, in the 4T1 system, optimal activity does not require MHC class II and CD80 expression in the vaccine cells. The cell-based vaccines were originally designed to activate tumor-s pecific CD4+ T lymphocytes specifically and thereby provide helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the therapy to fac ilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo depletion experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and tu mor challenge experiments in beige/nude/XID immunodeficient mice demonstrat e that the therapeutic effect is not exclusively dependent on a single cell population, suggesting that T and NK cells are acting together to optimize the response. IL-12 may also be enhancing the immunotherapy via induction of the chemokine Mig (monokine induced by interferon gamma), because revers e PCR experiments demonstrate that Mig is present in the lungs of mice rece iving therapy and is most likely synthesized by the tumor cells. These resu lts demonstrate that the combination therapy of systemic IL-12 and a cell-b ased vaccine is an effective agent for the treatment of advanced, dissemina ted metastatic cancers in experimental mouse models and that multiple effec tor cell populations and anti-angiostatic factors are likely to mediate the effect.