Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor-associated antigen) 5T4 induces active therapy of established tumors.
The human oncofetal antigen 5T4 (h5T4) is a transmembrane glycoprotein overexpressed by a wide spectrum of cancers, including colorectal, ovarian, and gastric, but with a limited normal tissue expression. Such properties make 5T4 an excellent putative target for cancer immunotherapy. The murine homologue of 5T4 (m5T4) has been cloned and characterized, which allows for the evaluation of immune intervention strategies in "self-antigen" in vivo tumor models. We have constructed recombinant vaccinia viruses based on the highly attenuated and modified vaccinia virus ankara (MVA strain), expressing h5T4 (MVA-h5T4), m5T4 (MVA-m5T4), and Escherichia coli LacZ (MVA-LacZ). Immunization of BALB/c and C57BL/6 mice with MVA-h5T4 and MVA-m5T4 constructs induced antibody responses to human and mouse 5T4, respectively. C57BL/6 and BALB/c mice vaccinated with MVA-h5T4 were challenged with syngeneic tumor line transfectants, B16 melanoma, and CT26 colorectal cells that express h5T4. MVA-h5T4-vaccinated mice showed significant tumor retardation compared with mice vaccinated with MVA-LacZ or PBS. In active treatment studies, inoculation with MVA-h5T4 was able to treat established CT26-h5T4 lung tumor and to a lesser extent B16.h5T4 s.c. tumors. Additionally, when C57BL/6 mice vaccinated with MVA-m5T4 were challenged with B16 cells expressing m5T4, resulting growth of the tumors was significantly retarded compared with control animals. Furthermore, mice vaccinated with MVA-m5T4 showed no signs of autoimmune toxicity. These data support the use of MVA-5T4 for tumor immunotherapy.
Mulryan
Kate
K
Cancer Research United Kingdom Immunology Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, M20 9BX, United Kingdom.
Ryan
Matthew G
MG
Myers
Kevin A
KA
Shaw
David
D
Wang
Who
W
Kingsman
Susan M
SM
Stern
Peter L
PL
Carroll
Miles W
MW
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D014408:Biomarkers, Tumor / Q000737:chemistry; D015153:Blotting, Western; D019496:Cancer Vaccines; D002469:Cell Separation; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008546:Melanoma, Experimental; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy*; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; C063709:trophoblastic glycoprotein 5T4, human