Combining tumor-targeted superantigens with docetaxel results in synergistic anti-tumor effects in B16 tumor bearing mice.

2075 In this study we explored the possibility of combining immunotherapy against cancer with the well-established cytostatic drug docetaxel. Tumor-targeted superantigens (TTS) utilizes the powerful T cell activating property of the superantigen staphylococcal enterotoxin A (SEA) in fusion with an anti-tumor Fab-fragment to target this T cell activity against tumor cells. TTS fusion proteins are efficient in a number of experimental tumor models including the B16 mouse melanoma transfected with a human tumor-associated antigen (GA733-2 or EpCam) recognized by the C215 monoclonal antibody. The distinct mechanisms of action of TTS and docetaxel provide the prerequisites for successful combination treatment. However, as a result of the anti-proliferative properties of cytostatic drugs, chemotherapy may potentially interfere with TTS immune activation during combination treatment. Here we evaluated the anti-tumor effects of combining the TTS protein C215Fab-SEA (4 daily injections of 10 μg/mouse i.v.) with docetaxel (1 mg/mouse i.p.) against B16-C215 tumors growing in the lung of C57Bl/6 mice. Both drugs showed a significant reduction in the number of lung tumors when administered alone. Prior treatment with docetaxel at therapeutic doses did not interfere with superantigen induced T cell activation but rather appeared to enhance the response, while simultaneous treatment was suppressive. Thus, docetaxel was given before or before and after the TTS cycle and these combinations significantly improved therapy further reducing the number of lung tumors as compared to mono therapies. In long term tumor survival experiments using the same tumor model, docetaxel treatment before and/or after one or two TTS treatment cycles synergistically prolonged the survival. When docetaxel was given before and after (days 2 and 9) C215Fab-SEA treatment (days 3-6), the prolonged median survival time of the combination treatment was more than 6.3 and 11.4 times the prolonged median survival times of C215Fab-SEA and docetaxel mono therapies, respectively. These results demonstrate that TTS immunotherapy is highly compatible with docetaxel and suggest a significant potential of the combination for human cancer therapy.