Immunotherapy with tumor-targeted superantigens (TTS) in combination with docetaxel results in synergistic anti-tumor effects |
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| Institution: | 3. University of Chinese Academy of Sciences, Beijing, 100049, China;1. School of Materials Science and Engineering, Harbin Institute of Technology, Harbin 150001, PR China;2. National Key Laboratory of Science and Technology on Precision Heat Processing of Metals, Harbin Institute of Technology, Harbin 150001, PR China;1. Uludag University School of Medicine, Department of Physiology, Bursa, Turkey;2. Uludag University School of Medicine, Department of Histology and Embryology, Bursa, Turkey;3. Uludag University School of Medicine, Department of Pharmacology, Bursa, Turkey;1. Graz Centre for Electron Microscopy, Steyrergasse 17, 8010 Graz, Austria;2. Institute for Geometry, Graz University of Technology, Kopernikusgasse 24, 8010 Graz, Austria;3. Institute of Electron Microscopy and Nanoanalysis, Graz University of Technology, Steyrergasse 17, 8010 Graz, Austria;1. Centre de Recherche de Biologie cellulaire de Montpellier (CRBM), CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier CEDEX 5, France;2. Sys2Diag, FRE3690-CNRS/ALCEDIAG, 1682 Rue de la Valsiere, 34184 Montpellier CEDEX 4, France;3. CNRS UMR5048, Centre de Biochimie Structurale, 29 rue de Navacelles, 34090 Montpellier, France;4. INSERM U1054, 34090 Montpellier, France;5. Université de Montpellier, 34090 Montpellier, France |
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| Abstract: | 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 a superantigen such as 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 modify TTS induced immune activation during combination treatment.Here we evaluated the anti-tumor effects of combining C215Fab-SEA with docetaxel against B16-C215 tumors growing in the lung of C57Bl/6 mice. Both compounds generated a significant reduction in the number of B16-C215 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. Combining TTS and docetaxel significantly improved tumor therapy, further reducing the number of lung tumors as compared to mono therapies. Importantly, the combination treatment at timely settings synergistically prolonged long term survival in B16-C215 tumor bearing mice. The results of this study demonstrate that TTS immunotherapy is highly compatible with docetaxel and suggest a significant potential of the combination for human cancer therapy. |
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