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Health

What a vaccine does

In the nearly 40 years since the nation declared war on cancer, great advances have been made in breast cancer screening, early detection and treatment.

The death rate for breast cancers has fallen.

More is discovered all the time about the genetics and biology of the disease.

But a cure remains elusive. Cancer, which is actually a variety of diseases, changes constantly and can spread throughout the body in ways that can be difficult to detect. Even when stopped in its tracks, it can often adjust and evade treatments that once worked against it.

In most cases, the body's immune system learns to go after a foreign invader like a virus or a bacteria.

But along with knowing what to attack, it knows what to ignore, namely those molecules that are part of the body. And that is what most tumors are: normal cells that have taken a bad turn and grown without controls.

Because the immune system sees cancer cells as part of the body, they avoid detection and destruction, leaving them free to invade breasts, bones, the brain and other major organs.

Johns Hopkins oncologist Dr. Leisha Emens' goal is to change that equation, to harness the power of the immune system to fight off breast tumors. Her design builds on work of colleagues at Hopkins and scientists at the Massachusetts Institute of Technology who determined through experiments with mice more than a decade ago that a vaccine using cancer cells genetically modified with a protein called granulocyte- macrophage-colony stimulating factor, or GM-CSF, could prevent tumors.

GM-CSF is something the body uses naturally to fight off illness.

In building a vaccine, Emens chose two separate lines of tumor cells from a repository in Washington for their ability to reproduce rapidly. Then she modified them to make and secrete GM-CSF at high levels.

She injected a small piece of DNA with the cells -- irradiated so they could not cause cancer -- to create the vaccine.

These cells are part of a mixture injected under the skin, 12 doses at a time, four times over the course of about six months. Once injected, the GMCSF- modified cells act as messengers, alerting the immune system to the presence of vaccine cells and drawing what are called dendritic cells to the vaccine site. Once the dendritic cells arrive, the vaccine cells are recognized as interlopers and are engulfed.

The dendritic cells now know to distinguish between tumor cells and normal cells and can teach this to the white blood cells known as T-cells. The Tcells then roam the body, and like Pac-Man can find and destroy breast cancer cells. T-cells commonly are used by the immune system to root out infection.

Emens' vaccine is made at a Food and Drug Administration- approved laboratory two floors below her office in a first-of-its-kind facility at a university.

The manufacturing process scales up the procedure Emens painstakingly did in her own laboratory when she created the vaccine. Whereas she did 100 million cells, the facility can grow 20 billion to 30 billion cells, enough to make vaccine for 25 patients.

All those cells are grown in a series of temperature- and humidity-controlled clean rooms, occupied by workers protected by gowns and gloves from head to toe. The first time a batch of vaccine was made for Emens in 2003, the facility created a master cell bank from the genetically modified cell lines Emens fashioned in her own lab. The master cell bank acts like a mold that an auto assembly plant would use to create a fender, allowing the vaccine to be created exactly the same way each time.

Now, when Emens requests more vaccine, the lab can transform a small number of cells into flasks of cells and then into many trays of cells, feeding them regularly with a nutritious substance that allows those many billions of cells to be grown in the matter of a week. None of the process is mechanized.

When completed, the vaccine is stored in a liquid nitrogen freezer until a patient arrives for her shots.

But the vaccine itself is not enough to halt cancer.

Something called regulatory T-cells get in the way.

They are essentially protecting the tumor from attack, since the body thinks the tumor is just another part of itself, something to be kept free from harm.

This is why Emens has given nearly all of the women in her two trials chemotherapy along with the vaccine.

The women in both Emens' first and second trials got a low dose of cyclophosphamide, a chemotherapy agent, the day before they received the vaccine. The cyclophosphamide is meant to knock down the regulatory T-cells so the T-cells can do their work. In the first trial of 28 women, Emens learned that the ideal dose of cyclophosphamide may be quite small, 200 mg/m2. Above that, the drug is more likely to kill off the very immune response the vaccine is attempting to achieve.

Emens is also trying different drugs a week after the vaccine is given to see what effects they might have on immune system response. The women in Emens' first trial received a chemotherapy drug called doxorubicin. The women in Emens' second trial -- which has enrolled 14 and is looking for six more patients with HER-2 positive breast cancer, a particularly aggressive type -- receive a drug called Herceptin, which Emens calls one of the great recent advances in treating breast cancer.

The timing of when the various drugs are given during the trials came out of mouse models. When mice got the same treatment as the women in the first trial, about 30 percent were cured of their tumors.

When they got what Emens is giving the patients in the second trial, between 55 percent and 60 percent of the mice were cured. Finding the right combination of medications to give to improve the efficacy of the vaccine could be a key to its success.

"Folks have a tendency to add a vaccine to standard treatments without really considering how they might interact," Emens said.

Whether the vaccine is working can be measured in a variety of ways. Emens looks in the blood for antibodies and T-cells. She also looks at scratch tests done with a protein in the vaccine that would show a systemic response. If the area around the test gets red and swollen, there has been an immune reaction.

Copyright © 2014, The Baltimore Sun
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