Adenovirus-mediated intratumoral lymphotactin gene transfer potentiates the antibody-targeted superantigen therapy of cancer.
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.
Wang
Qingqing
Q
Institute of Immunology, Zhejiang University, 353 Yan'an Road, Hangzhou 310031, P.R. China.
Yu
Hai
H
Zhang
Lihuang
L
Ju
Dianwen
D
Pan
Jianping
J
Xia
Dajing
D
Yao
Hangping
H
Zhang
Weiping
W
Wang
Jianli
J
Cao
Xuetao
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D002460:Cell Line; D017690:Cell Transplantation; D019744:Chemokines, C; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D018014:Gene Transfer Techniques; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000235:genetics* / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012795:Sialoglycoproteins / Q000235:genetics* / Q000276:immunology; D018089:Superantigens / Q000276:immunology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019744:Chemokines, C; D016207:Cytokines; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D008222:Lymphokines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; D018089:Superantigens; C092390:XCL1 protein, human; C486249:Xcl1 protein, mouse; C018997:lymphotactin; C026066:enterotoxin A, Staphylococcal