© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 2, 169-175,
January 20, 1999
© 1999 Oxford University Press
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Induction of Tumor Antigen-Specific Immunity In Vivo by a Novel Vaccinia Vector Encoding Safety-Modified Simian Virus 40 T Antigen
Affiliations of authors: Y. C. Xie, C. Hwang, Z, Zeng, M. H. Eng, J. J. Mulé (Department of Surgery and the Comprehensive Cancer Center), M. J. Imperiale (Department of Microbiology and Immunology), The University of Michigan, Ann Arbor; W. Overwijk, N. P. Restifo, Surgery Branch, National Cancer Institute, Bethesda, MD; M. G. Sanda, Department of Surgery (Urology) and the Comprehensive Cancer Center, and Department of Medicine (Oncology), The University of Michigan, and Surgery Service-Urology Section, Ann Arbor Veterans Administration Medical Center, Ann Arbor.
Correspondence to: Martin G. Sanda, M.D., Department of Surgery (Urology), University of Michigan, 1500 E. Medical Center Dr., 2916 Taubman Center, Ann Arbor, MI 48109-0330 (e-mail: msanda{at}umich.edu).
BACKGROUND: Evidence that simian virus 40 (SV40) is associated with human mesotheliomas, osteosarcomas, and brain tumors suggests that a recombinant vaccine directed against lethal cancers expressing SV40 T antigen (Tag) could have clinical utility. To address this potential need, we designed a novel vaccinia virus construct that encodes an SV40 Tag in which oncogenic domains were excluded and immunogenic domains were preserved. We named this recombinant construct vaccinia-encoding safety-modified SV40 Tag (vac-mTag). METHODS: Purified vac-mTag was characterized by DNA sequencing, reverse transcription-coupled polymerase chain reaction, western blot analysis, and immunocytochemical techniques. Induction of Tag-specific immunity was examined by cytolytic T-cell assays, and the efficacy of vac-mTag in protecting animals against Tag-expressing tumors and in treating pre-established microscopic tumors was evaluated in vac-mTag-immunized BALB/c mice. RESULTS: The immune response elicited by vac-mTag in C57BL/6 and BALB/c mice included an SV40 Tag-specific cytolytic T-lymphocyte activity against syngeneic (identical genetic background) SV40 Tag-expressing tumor targets. Immunization of mice with a single dose of vac-mTag resulted in potent protection against subsequent challenge with a lethal mouse cancer expressing SV40 Tag. In addition, single-dose vac-mTag immunization coadministered with interleukin 2 produced a possible therapeutic effect against a preadministered microscopic (but lethal) burden of Tag-expressing tumor cells in vivo. CONCLUSION: vac-mTag induces an effective immune response in mice that is specific for a tumor-associated antigen. This response protects against a lethal tumor challenge and results in a possible therapeutic effect against Tag-expressing tumors in vivo. Thus, vac-mTag provides a new avenue for the development of therapies for human cancers thought to be associated with SV40.
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