Immune to cancer
by Amy Adams
Illustration by Richard Beards

Stanford researchers put the immune system to work in treating

The immune system is good at many things: fighting infections, eradicating bacteria, even fending off colds most of the time. But when it comes to cancer, the body’s natural defenses turn a blind eye.

The problem is that immune cells fight only foreign objects such as virus, bacteria or transplanted organs — and cancer cells aren’t foreign; they are a normal part of the body gone haywire. Tricking the immune system into attacking cancer involves a molecular sleight-of-hand to turn familiar cells into a recognizable disease.

Although researchers have had some success using the immune system in cancer treatment, they have yet to hoodwink the body’s defenses into recognizing myeloma — a cancer of the immune cells known as B cells that hang out in the bone marrow.

But a new way of using a classic vaccine technique might turn that luck around. The technique, being developed by Keith Stockerl-Goldstein, MD, combines a myeloma vaccine with a new form of bone marrow transplant. The research is still under way, but experts think this combined approach could eventually turn an incurable cancer into one with good odds of remission.

The standard treatment for myeloma is high-dose chemotherapy and radiation. Together, these protocols indiscriminately wipe out normal and cancerous bone marrow cells alike. "This is essentially a lethal dose," says Stockerl-Goldstein, an assistant professor of medicine. Doctors bring patients back from this precipice by replenishing their immune systems with stem cells purified from their blood before treatment began.

About 20 percent of patients go into complete remission after this treatment. However, even with the intense chemotherapy and radiation, some myeloma cells remain. These cells eventually begin dividing and the cancer resurges stronger than before, this time resistant to chemotherapy.

Looking at this high relapse rate, Stockerl-Goldstein began thinking about the work of oncologist Ronald Levy, MD, the Robert K. and Helen K. Summy Professor in the School of Medicine. "He had been doing work with vaccines for lymphoma," Stockerl-Goldstein says. "The thought was that because lymphoma and myeloma are relatives, maybe there’s a way to take advantage of Levy’s work." Like myeloma, lymphoma is a disease of the B cells. What differentiates the two diseases is the point in the B-cell life cycle at which the cells become cancerous. If a young B cell becomes cancerous, the result is lymphoma. If a more mature cell becomes cancerous, myeloma arises.

Mature B cells serve one very specific role in the immune system. "That cell’s job in life is to make a lot of protein and shoot it into the blood," says Stockerl-Goldstein. Each B cell makes a different protein — called an idiotype — with the exception of the myeloma cells. Because the myeloma cells all came from a single parent, they all mass-produce the same idiotype. Better yet, as far as immunotherapy is concerned, they all wear pieces of that unique protein on their cell surface, like a molecular signpost reading "cancer here." The goal of the vaccine is to teach the immune system to read that sign and then kill off the cancerous cells.

A vaccine to fight myeloma

All vaccines work by introducing immune cells to a target molecule in the hope that the cells will learn to identify — and fight — that molecule in the future. But unlike a one-size-fits-all flu vaccine that protects all people equally, a cancer vaccine must be specific for each person’s cancer. "Making a vaccine for somebody with myeloma is not like giving a flu or a tetanus vaccine where every person gets the same injection," Stockerl-Goldstein says. "Each person’s myeloma cells produce a distinct protein that is different from the protein produced by anybody else with myeloma. This means that a vaccine must be individually produced for each."

Stockerl-Goldstein makes his vaccine out of the very protein the myeloma cells mass-produce. "We take six to eight tubes of blood from the patient and we have the vaccine," he says. Or, more accurately, he has the beginnings of a vaccine. If he simply injected that protein back into the blood it would be indistinguishable from the protein that’s already there. Instead, Stockerl-Goldstein reintroduces the idiotype to the body using the immune system’s own method for highlighting foreign molecules — a technique Levy had used successfully in treating lymphoma.

One branch of the immune system — the T cells — learns what is foreign with the help of a specialized group of cells called dendritic cells. These dendritic cells wander the bloodstream gobbling up suspect proteins and displaying the molecular bits on their cell surface. The T cells then inspect these protein chunks and use them as a guide for what to go after next.

Stockerl-Goldstein hijacks this system by feeding the myeloma idiotype to a dendritic cell in a lab dish. "That makes the myeloma idiotype into a recognizable foreign substance," he says. He then injects that idiotype-studded dendritic cell back into the patient’s body. Now T cells that had been living in harmony with the myeloma’s idiotype see it on the surface of a dendritic cell and mount a defense against it. Eventually their hunt leads them to the idiotype-producing cells themselves, hunkered down in the bone marrow. The T cells kill off the lurking myeloma and the patient is cancer-free.

Or at least that’s the theory. By 1999 Stockerl-Goldstein and Levy had tested their vaccine in 12 patients and had seen some promising results but the T cells weren’t responding as quickly or as vigorously as the researchers had expected. The problem, they thought, was that the dendritic cells had come from the patient’s own faltering immune system. These are not the hale and hearty cells they’d prefer to offer the ailing patients. "That’s why our new idea is to use a healthy source of dendritic cells," Levy says. The healthy source will be a sibling with an immune system that closely matches the patient’s.

Sibling Rivalry

Their new strategy combines the vaccine work with an alternative form of bone marrow transplant that researchers at Stanford, Fred Hutchinson Cancer Research Institute and City of Hope Cancer Center have been testing. First, patients get chemotherapy to knock out their immune system, bone marrow and myeloma, followed by a transplant of their own bone marrow. This is the traditional therapy that results in a temporary remission. But before the cancer cells can bounce back, the patients get whole-body radiation to demolish their recovering immune systems, followed by a transplant of a sibling’s bone marrow stem cells. The sibling’s cells then repopulate the bone marrow and eventually take over the patients’ immune systems.

Why the double whammy? Doctors regularly give lymphoma patients bone marrow from a sibling and the patients recover well. But when Stockerl-Goldstein and researchers elsewhere gave myeloma patients such a transplant only half of the patients survived. Though these survivors had remarkable remission rates, the risk of death due to the transplant itself was too high for researchers to use the technique for myeloma.

Stockerl-Goldstein and Levy wanted to have their cake and eat it too; they wanted the good transplant survival rates of the standard therapy combined with the high remission rates that come from the sibling transplants. By doing the first transplant with the patient’s cells, followed by a transplant with the sibling’s cells they achieved success — good survival and a remission rate that skyrocketed from 20 percent to 60 percent.

The reason for that impressive remission rate lies in the sibling’s immune system. "Once you put the immune system into the patient, it does not know it’s in a new environment," Stockerl-Goldstein says. The sibling’s immune system, thinking that it is still in the sibling, sees every cell and every organ as being foreign and goes on the offensive. This response is called graft-versus-host disease and is more or less the opposite of what takes place when a person rejects a transplant. Same process, but in this case the transplant rejects the body. Normally, graft-versus-host disease is something doctors work to avoid, but not so here. "People who get some graft-versus-host disease have a lower chance of their cancer coming back," Stockerl-Goldstein says. "So what we try to do is find some balance."

Some balance, that is, between a total rejection of the patient’s body and a rejection only of the cancer cells. Balance comes via drugs that weaken the new immune system enough to stop it from attacking anything major, like the heart or brain, but leave it strong enough to go after the myeloma cells.

"The myeloma goes into remission over a period of months," Stockerl-Goldstein says. It can take as long as nine months for the sibling’s immune system to drive out the myeloma. Because some of the 32 patients in the trial received their vaccine treatments only recently, Stockerl-Goldstein thinks the remission rate may go up over time. "It’s still relatively early," he says.

Hope for success with combined approach

A 60 percent remission rate compared with the usual 20 percent is nothing to scoff at. "But that’s still 40 percent of people who don’t go into remission," Stockerl-Goldstein says. "At the end of this we’re looking for more people in remission and more people surviving," he says.

To achieve this end, Stockerl-Goldstein and Levy are adding their dendritic cell vaccine to the two transplants, this time using the sibling’s dendritic cells. "Now that we have a new immune system we want to make it more effective." Stockerl-Goldstein says. The vaccine should help make the graft-versus-host response more targeted to the myeloma cells. Levy agrees, "If we can make it work, we think good things will happen for the patient."

So far they’ve used the dendritic cell vaccine in only one patient who had the double transplant and it’s too early to assess that patient’s response. Despite the study’s relative youth, their colleague Robert Negrin, MD, is hopeful.

"The idea that you can direct a donor immune system to detect the cancer is a novel approach," says Negrin, an associate professor of medicine and director of the bone marrow transplant division. "Now we are talking about the possibility of curing this type of cancer," Negrin says. "That’s something that has not been talked about before."

SM

This document was last modified: Wednesday, 31-Dec-1969 16:00:00 PST
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