SV40 Vaccine Shows Promise in Mesothelioma

CHICAGO—A 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 domains—thought to be responsible for stimulating S phase entry, prevention of apoptosis, and induction of chromosomal damage—are 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 virus.

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 more effective."

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.