Adenovirus-mediated intratumoral lymphotactin gene transfer potentiates the antibody-targeted superantigen therapy of cancer.

Abstract

Bacterial superantigens are extremely potent activators of murine and human T lymphocytes. To engineer superantigens for cancer immunotherapy, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the human colon carcinoma-reactive monoclonal antibody (mAb) C215. Fusion protein C215Fab-SEA can trigger cytotoxic T cells against C215 antigen positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is often not satisfactory because of T cell deletion after activation and failure to induce potent CTL activity after repeated administration. Lymphotactin (Lptn) is a potent chemoattractant for T cells and NK cells. To improve the therapeutic efficacy of fusion protein C215Fab-SEA we investigated in this study the antitumor responses elicited by combination of C215Fab-SEA and adenovirus-mediated intratumoral Lptn gene transfer in the preestablished C215 antigen expressing B16 melanoma murine model. More significant inhibition of tumor growth and prolonged survival time were observed in tumor-bearing mice that received combined therapy of C215Fab-SEA and Ad-Lptn than those of mice treated with C215Fab-SEA or Ad-Lptn alone. The highest CTL activity of tumor-bearing mice was induced after combined therapy. Intratumoral coadministration of C215Fab-SEA and Ad-Lptn augmented splenic NK activity of tumor-bearing mice most markedly. Our data demonstrate that the in vivo antitumor effect of C215Fab-SEA immunotherapy is potentiated significantly by combination with intratumoral Lptn gene transfer through more efficient induction of specific and nonspecific antitumor immune responses.

• Authors: Qingqing Wang, Hai Yu, Lihuang Zhang, Dianwen Ju, Jianping Pan, Dajing Xia, Hangping Yao, Weiping Zhang, Jianli Wang, Xuetao Cao
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 80 Issue 9 Pg. 585-94 (Sep 2002) ISSN: 0946-2716 [Print] Germany
• PMID: 12226740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• Chemokines, C
• Cytokines
• Enterotoxins
• Immunoglobulin Fab Fragments
• Lymphokines
• RNA, Messenger
• Recombinant Fusion Proteins
• Sialoglycoproteins
• Superantigens
• XCL1 protein, human
• Xcl1 protein, mouse
• lymphotactin
• enterotoxin A, Staphylococcal

Topics

• Adenoviridae (genetics)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antigens, Neoplasm (immunology)
• Cell Line
• Cell Transplantation
• Chemokines, C
• Combined Modality Therapy
• Cytokines (biosynthesis)
• Enterotoxins (immunology, therapeutic use)
• Female
• Gene Transfer Techniques
• Immunoglobulin Fab Fragments (immunology, therapeutic use)
• Killer Cells, Natural (immunology)
• Lymphocyte Activation
• Lymphokines (genetics, immunology)
• Male
• Melanoma, Experimental (immunology, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (immunology)
• RNA, Messenger (genetics, metabolism)
• Recombinant Fusion Proteins (therapeutic use)
• Sialoglycoproteins (genetics, immunology)
• Superantigens (immunology, therapeutic use)
• T-Lymphocytes, Cytotoxic (immunology)
• Tumor Cells, Cultured