Combination treatment of murine tumors by adenovirus-mediated local B7/IL12 immunotherapy and radiotherapy

Failure of local tumor control still poses a problem for radiotherapy and t ranslates into reduced survival. Combining radiation with chemotherapy or o ther newer modalities has shown promising results. Immunological approaches to tumor therapy have found renewed interest due to improved insight into mechanisms involved in the immune response to tumors. In this paper, we stu died tumor growth delay after various combination regimens of locally injec ted adenovirus constitutively expressing IL12 and B7.1 (AdIL12/B7.1) and fr actionated radiotherapy in two nonimmunogenic murine tumor models, 4T1 and B16.F10. Effects of radiation and virus infection on surface antigen expres sion in these tumor lines were assessed. Mechanisms of action of AdlL12/B7. 1 were studied by conducting additional experiments with and without deplet ion of NK-cells and/or T-cells, and by cytotoxic T-lymphocyte assays, and i mmunohistochemical evaluation of tumor blood vessels. Both B7.1 and IL12 we re effectively expressed in both irradiated and unirradiated 4T1 and B16.F1 0 tumor cells but did not add significantly to radiation-induced cell killi ng in vitro. However, local tumor infection by AdIL12/B7.1 after irradiatio n significantly increases the effectiveness of radiotherapy when applied af ter completion of radiotherapy. The mechanism appears to be complicated, in volving a host of factors that included the ability of IL12 to activate T-c ells and NK-cells and to inhibit angiogenesis and the ability of radiation to induce apoptosis or necrosis among tumor cells. These data support the c ombination of radiotherapy with adenovirus-mediated immunotherapy and sugge st that the concept of adding genetic immunotherapy after radiotherapy in a combined regimen merits further study.