Herpes-Based Gene Therapy Is Key To Promising Liver Tumor Vaccine

April 03, 1997

Physicians from the University of Rochester's Cancer Center and Memorial Sloan-Kettering Cancer Center have created a promising compound that recruits the body's immune system to target and wipe out cancer cells in the liver. In a study with laboratory rats, the majority of animals injected with the vaccine were cancer-free, while similar animals that did not receive the vaccine typically had dozens of tumors. The work was reported in a recent issue of the Journal of Clinical Investigation.

Work on cancer vaccines is designed to focus the full force of the body's immune system on the area of the body under attack by cancer. While such research is widespread, this vaccine is one of the first to be created using gene therapy and to target liver cancer. It's also rare for a vaccine to completely eliminate the formation of cancerous tumors in animals or humans.

Lead author of the report is Yuman Fong, M.D., one of the world's leading liver cancer surgeons, at Memorial Sloan- Kettering Cancer Center in New York City. Other authors include Howard Federoff, M.D./Ph.D., chief of the University of Rochester's Division of Molecular Medicine and Gene Therapy and professor in the Department of Neurology; Michael Brownlee, M.D., of the Albert Einstein College of Medicine; and Sloan-Kettering physicians Howard Karpoff, Michael D'Angelica, and Sarah Blair.

"We have been searching for a vaccine against liver cancer because the disease is so relentless given today's therapies," says Dr. Fong. The disease, striking more than two million people annually, is usually treated surgically, but in a majority of cases the cancer returns and usually spreads more rapidly after surgery. Sloan-Kettering surgeons have pioneered methods to boost the immune system in such patients, in an effort to aid the body in ridding itself of cancer cells. The group turned to Dr. Federoff in an effort to use gene therapy to supplement the body's immune response.

The modified cells created by Drs. Federoff and Fong act as a beacon to the body's immune system, attracting to the liver great numbers of immune cells that have developed specially in response to the tell-tale proteins found on the surface of cancer cells. In theory, the sheer numbers of these cells should wipe out any stray cancer cells that escaped the surgeon's knife. A compound that does this, such as the vaccine cocktail put together by Drs. Federoff and Fong, is known as an autologous tumor vaccine.

"We're trying to exploit the immune system's ability to specifically recognize and kill tumor cells," says Dr. Federoff.

The physicians used a herpes simplex virus -- the same one that causes blisters and cold sores in people and animals, only modified so that it can't replicate -- to send into rats genes that code for substances known as cytokines. Cytokines beckon the body's immune system to mount an attack against a foreign substance. Doctors also injected the rats with gamma-interferon, another cytokine now used clinically to help the body fight cancer. Then they measured the rats' resistance to cancer cells.

Doctors found that inserting into cells a gene to boost the cytokine interleukin-2 (IL2) along with the gamma-interferon treatment was a very effective combination, completely preventing tumors from forming in 8 of 11 rats. IL-2 stimulates the formation of lymphocytes known as cytotoxic T cells, which are especially effective at killing cancer cells. The team also achieved noteworthy results by raising the levels of the cytokine GMCSF (granulocyte macrophage colony stimulating factor), which attracts macrophages: 4 of 12 rats remain cancer-free.

High cytokine levels peak on the first day, Dr. Federoff says, and remain high for a couple of days before falling off and eventually returning to normal. The short duration and targeted scope of the high levels are key: Such high levels of cytokines in the entire body would be toxic to most people and animals.

It takes the herpes simplex viral amplicon vectors only about 20 minutes to slip genes into cells, Dr. Federoff says, much faster than other gene delivery methods like retroviruses. That's fast enough for cells to be modified and put back into a patient during the same surgical procedure to remove the cancer.

"The beauty of the herpes system is that it's so simple and relatively rapid," says Dr. Federoff, a world leader in the use of herpes particles in gene therapy. He and Dr. Fong hope to try the therapy on human patients in the future.
-end-


University of Rochester

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