Combining tumor-targeted superantigens with interferon-alpha results in synergistic anti-tumor effects.
In this study we explored the possibility of improving the anti-tumor potency of tumor-targeted superantigens (TTS) by combination treatment with interferon-alpha (IFN-alpha). 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 have shown anti-tumor efficacy in a number of experimental tumor models including the B16 mouse melanoma transfected with a human tumor-associated antigen recognized by the C215 monoclonal antibody. IFN-alpha is approved for the treatment of solid tumors such as renal cell carcinoma and malignant melanoma and exerts immunomodulatory effects, which make it an appropriate candidate to combine with immunotherapy against cancer. Here we report that daily administration of IFN-alpha (20 000 U i.p.) enhances and sustains CD8+ T cell activation induced by the TTS C215Fab-SEA (10 microg i.v.) in C57Bl/6 mice, as reflected by increased and prolonged cell-mediated cytotoxicity against tumor cells ex vivo as well as by augmented serum IFN-gamma levels. C215Fab-SEA synergized with IFN-alpha in reducing the number of lung tumors in B16-C215 melanoma bearing mice as compared to mono therapy. In a long term tumor survival experiment, the prolonged median survival time of the combination treatment was 3.5 and 7.7 times the prolonged median survival times of C215Fab-SEA and IFN-alpha monotherapies, respectively. Hence, the combination treatment provoked synergistic anti-tumor effects as measured by the number of lung tumors and markedly prolonged survival. The enhanced therapeutic efficacy correlated with a striking and sustained increase of CD8- and perforin-expressing tumor-infiltrating cells. These results suggest significant potential of combining TTS with IFN-alpha for human cancer therapy.
Sundstedt
Anette
A
Active Biotech Research AB, P.O. Box 724, SE-220 07 Lund, Sweden. anette.sundstedt@activebiotech.com <anette.sundstedt@activebiotech.com>
Celander
Mona
M
Hedlund
Gunnar
G
D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000008:administration & dosage*; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018089:Superantigens / Q000008:administration & dosage*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D016898:Interferon-alpha; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma