CHICAGOA vaccinia-based vaccine against a modified
simian virus 40 (SV40) large T antigen has proven efficacious in animal models,
said Michael Imperiale, PhD, professor of microbiology and immunology,
University of Michigan Medical School, Ann Arbor. He described the vaccine at a
conference on the role of SV40 in malignant mesothelioma, sponsored by the
University of Chicago.
The vaccinia-mTAg vaccine was designed bearing in mind that
specific domains of the large T antigen are oncogenic. While the domains
required for antigenicity are retained in this vaccine, the transforming
domainsthought to be responsible for stimulating S phase entry, prevention
of apoptosis, and induction of chromosomal damageare removed, leaving the
antigenic epitopes preserved.
According to Dr. Imperiale, the vaccine satisfies in vitro
safety assays for oncogenic potential, including the inability to induce focus
formation in 3T3 cells and the inability to induce anchorage-independent growth
in cultured murine fibroblasts.
Antigenic epitopes of the vaccine successfully induced T-cell
immunity in an animal model, and the vaccine was effective in slowing tumor
growth and prolonging survival of mice with implanted tumors from in
vitro-derived tumor lines (see Figure).
In a postconference interview, Dr. Imperiale responded to
potential concerns that smallpox-experienced patients may have circulating
vaccinia-neutralizing antibodies. He said that he was aware of the potential
difficulty and is exploring alternative delivery vehicles such as fowlpox
Dr. Imperiale also countered concerns about the potential of
T-antigen-negative cells to escape the immune response. "There is no
evidence in animal models that such variant cells arise at high enough levels
to regrow into tumors," he said.
He argued that although mesotheliomas in culture may lose SV40
DNA sequences, there is no certainty that this will happen in patients, since
cultured mesotheliomas undergo additional selective events.
"In addition," Dr. Imperiale said, "if
T-antigen-negative cells do exist, the vaccine should at least reduce the tumor
burden enough to where other adjuvant therapies, such as chemotherapy, might be
The SV40 vaccine will be tested in malignant mesothelioma
patients in a phase I dose-escalation trial that is currently under
development, funded by a grant through the Rapid Access to Intervention
Development (RAID) mechanism of the National Cancer Institute.