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

• Published in: International journal of cancer Vol. 81; no. 1; pp. 156 - 163
• Main Authors: Rosendahl, Alexander, Kristensson, Karin, Carlsson, Mats, Skartved, Niels Jørgen, Riesbeck, Kristian, Søgaard, Morten, Dohlsten, Mikael
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 31.03.1999; Wiley-Liss
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Drug Synergism; Enterotoxins - pharmacology; Female; Immunoglobulin Fragments - pharmacology; Immunotherapy; Immunotoxins - pharmacology; Interferon-gamma - biosynthesis; Interleukin-2 - pharmacology; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Time Factors; Tumor Necrosis Factor-alpha - biosynthesis; Animal model; Spontaneous; Cytokine; Rodentia; Malignant tumor; Monoclonal antibody; Fab-Fragment; Long term; Survival; Staphylococcus; Vertebrata; Mammalia; Treatment; Interleukin 2; Mouse; Animal; Immunotherapy; B16-Melanoma; Established cell line; Enterotoxin; Superantigen; Bacteria; Micrococcales; Micrococcaceae
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19990331)81:1<156::AID-IJC25>3.0.CO;2-H

The bacterial superantigen (SAg) staphylococcal enterotoxin A (SEA) is a potent inducer of CTL activity and cytokine production in vivo. To engineer SAg for cancer immunotherapy, we genetically fused SEA to a Fab fragment of the C215 tumor‐reactive antibody. Strong reduction of lung metastasis was seen in mice carrying established lung metastases of the poorly immunogenic B16‐C215 melanoma after Fab–SEA therapy. However, important anti‐tumor effector functions, such as IFN‐γ secretion and CTL activity, gradually declined during therapy. In this study, we show that Fab–SEA immunotherapy is strongly potentiated by Fab–IL‐2 co‐administration. Combined Fab–IL‐2 and Fab–SEA therapy prolongs the immune response in vivo, limits the development of immunological unresponsiveness and promotes maximal anti‐tumor effects. Significantly prolonged survival was noted in tumor‐carrying animals treated with Fab–SEA/ Fab–IL‐2 as compared with Fab–SEA or Fab–IL‐2 alone. Combination 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 cycles of treatment. In contrast, the immune response after combination therapy was characterized by substantially augmented IFN‐γ and TNF‐α production and strong CTL activity. Our data demonstrate that combined Fab–SEA and Fab–IL‐2 therapy prolongs the immune response in vivo and induced long‐term survival of more than 90% of the animals carrying the highly aggressive B16 melanoma. Int. J. Cancer 81:156–163, 1999. © 1999 Wiley‐Liss, Inc.