Long-term survival and complete cures of B16 melanoma-carrying animals after therapy with tumor-targeted IL-2 and SEA

The bacterial superantigen (SAg) staphylococcal enterotoxin A (SEA) is a po tent inducer of CTL activity and cytokine production in vivo. To engineer S Ag for cancer immunotherapy, we genetically fused SEA to a Fab fragment of the C215 tumor-reactive antibody. Strong reduction of lung metastasis was s een in mice carrying established lung metastases of the poorly immunogenic B16-C215 melanoma after Fab-SEA therapy, However, important anti-tumor effe ctor functions, such as IFN-gamma secretion and CTL activity, gradually dec lined during therapy. In this study, we show that Fab-SEA immunotherapy is strongly potentiated by Fab-IL-2 coadministration. Combined Fab-IL- 2 and F ab-SEA therapy prolongs the immune: response in vivo, limits the developmen t of immunological unresponsiveness and promotes maximal anti-tumor effects . Significantly prolonged survival was noted in tumor-carrying animals trea ted with Fab-SEA/Fab-IL-2 as compared with Fab-SEA or Fab-IL-2. alone. Comb ination therapy resulted in complete cure in 90% of tumor-bearing animals, whereas only 10% long-term survival was seen in Fab-SEA or Fab-IL-2-treated animals. Single Fab-SEA therapy induced a hyporesponsive state after 2 cyc les of treatment, In contrast, the immune response after combination therap y was characterized by substantially augmented IFN-gamma and TNF-alpha or p roduction and strong CTL activity. Our data demonstrate that combined Fgb-S EA and Fab-IL-2 therapy prolongs the immune response in vivo and induced lo ng-term survival of more than 90% of: the animals carrying the highly aggre ssive B16 melanoma. (C) 1999 Wiley-Liss, Inc.