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Gene work could aid vaccines, cancer therapy

Researchers at the Whitehead Institute for Biomedical Research and Boston's Children's Hospital have found a new way to rev up the engines of the mammalian immune system.

They have taken an organism used worldwide to vaccinate against tuberculosis and packaged inside it mammalian genes that stimulate immune cell function. This achievement could lead to more effective vaccines for a broad range of human diseases and also--because the same organism is used in immunotherapy for bladder cancer--to safer, more effective cancer therapy.

In the January 23 issue of Proceedings of the National Academy of Sciences, Dr. Peter Murray and his coworkers describe how they inserted five different immune system growth factor genes into BCG (bacille Calmette-Guerin), the organism used for decades to elicit a protective immune response against tuberculosis. The proteins produced by these genes, called cytokines, are natural immune stimulators: they activate disease-fighting cells and enhance their response to bacteria and other foreign substances in the body.

Dr. Richard Young, leader of the Whitehead group and professor of biology at MIT, said, "BCG by itself is a powerful immune stimulant so we were surprised to see just how much additional power we could get with the recombinant BCG.

"If you think of the immune response as many battalions of white blood cells armed and ready to fight infection, then the effect of the transformed BCG is to give each battalion extra allotments of ammunition," Dr. Young added. "In mice, we found that some of the transformed strains elicit immune responses 10 times greater than those elicited by normal BCG."

The new Whitehead study represents the first systematic effort to determine which mammalian growth factors might be most suitable for a new BCG recombinant vaccine for tuberculosis and other diseases.

In most human societies, tuberculosis is the leading cause of death among infectious diseases. The World Health Organization estimates that one-third of the human population is infected with tuberculosis. Generally, the body's natural response to the tuberculosis bacterium suppresses the infection, but a small percentage of infected individuals develop clinical symptoms and 1 to 3 million people die each year from the disease.

Early in this century, researchers in France demonstrated that a weakened strain of the bacterium responsible for cow tuberculosis could provide some protection against human TB when administered as a vaccine. This weakened bacterium was named BCG in honor of its discoverers, Leon Calmette and Camille Guerin. BCG vaccines have been administered to more than 2 billion people worldwide.

"BCG vaccines have a long record of safe use, but their reported efficacy varies tremendously," said Dr. Murray, the Whitehead postdoctoral fellow who is first author of the PNAS paper. "Depending on the vaccine trial, efficacy figures range from 0 to 80 percent. Such variability, combined with the increase in drug-resistant TB cases worldwide, underscores the need for an improved TB vaccine."

In the current study, Drs. Young and Murray and Dr. Anna Aldovini of Children's Hospital and Harvard Medical School showed that after 16 weeks, immune cells from mice injected with three BCG recombinants reacted much more vigorously to challenge with TB-related proteins than immune cells from mice injected with standard BCG. The three BCG recombinant strains secreted the mouse immune growth factors interleukin-2 (IL-2), interferon gamma (IFN-g), and granulocyte macrophage colony stimulating factor (GM-CSF).

Future experiments will explore whether the enhanced response is due to an increase in the number of immune cells that recognize BCG or to increased activity of a small subset of immune cells. The Whitehead scientists will also begin to hone in on the ideal genetic make-up of an improved TB vaccine for human beings.

"This work has important implications for many different infectious diseases, not just TB," Dr. Young said. "Several years ago, we demonstrated in mouse studies that we could elicit a varied immune response against HIV proteins by inserting the genes for these proteins into BCG and injecting the BCG/HIV recombinants into mice. [HIV, or human immunodeficiency virus, is the agent that causes AIDS.] If we could make these responses stronger, we might have more effective vaccines for a variety of diseases, including AIDS."

One way of accomplishing this may be to construct BCG strains that carry both HIV genes and the most potent cytokine genes. Dr. Young and his colleagues already are pursuing this project. A similar strategy could lead to new and better vaccines for childhood diseases such as tetanus and whooping cough.

The new BCG recombinants also could help the body fight off tumor cells. Urologists have found that many cases of superficial bladder cancer respond to treatment with large doses of BCG delivered directly into the bladder by a catheter. The immune response to the BCG appears to help the body recognize and destroy tumor cells, but the exact mechanism remains a mystery.

Dr. Michael O'Donnell, a researcher and urologist at Boston's Beth Israel Hospital and Harvard Medical School who worked with the Whitehead group developing the first IL-2 secreting recombinants, explained: "To achieve a therapeutic effect with conventional BCG, we usually give high doses of BCG for prolonged periods. This creates a real, albeit small chance of substantial toxicity because BCG is disseminated into the bloodstream, essentially mimicking systemic tuberculosis. These high doses are also problematic because there is mounting evidence that too much BCG may impair the 'anti-cancer' immune response we are trying to achieve.

"Thus, there is a great need for BCG strains that are both more effective and more reliable than current strains at lower doses," Dr. O'Donnell added. "The BCG recombinants carrying cytokine genes may meet this need-providing the additional ingredients to 'jump-start' or accelerate the body's natural immune defense system while minimizing the actual dose of BCG required."

"Cytokines alone are powerful immune stimulants," Dr. Aldovini added. "In some cases, they are being injected directly into the bloodstream to treat metastatic kidney cancer, malignant melanoma and other life-threatening diseases. But the side effects can be very severe. The cytokine-secreting BCG may provide an alternative delivery system, allowing physicans to boost the immune response at specific sites and thus avoiding the toxicity that often accompanies systemic therapy."

This work was supported by the US Public Health Service and by a C.J. Martin Fellowship to Dr. Murray from the National Health and Medical Research Council of Australia.

A version of this article appeared in MIT Tech Talk on January 24, 1996.

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