Taking a Jab at Cancer

Combined with drugs, vaccines against tumors may finally be working

Imagine a patient getting a vaccine injection in the doctor’s office—but not to ward off a virus or a bacterium that causes smallpox, measles, or any other infectious disease. This vaccine is for cancer, specifically for a tumor already growing within the patient’s body. The treatment, perhaps in combination with others, is intended to train the patient’s immune system to recognize and kill malignant cells.

THE CURE WITHIN. This multilobed killer T cell, part of the immune system, is destroying a cancer cell. But tumors can undermine such attacks. G. Kaplan/Univ. of Medicine and Dentistry of New Jersey

WEB OF DECEIT. Tumor cells send out chemical signals such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and cyclooxygenase-2 (COX2) that reduce the immune system’s attack on the cancer. Activation steps (arrows) and inhibition (lines with bars) boost regulatory T cells, curb killer T cells, and stifle the maturation of dendritic cells. Immature dendritic cells and stimulated regulatory Ts further subdue the antitumor response of the killer Ts. E. Roell

It’s a strategy that scientists have been working on for more than 15 years, but rallying the immune system to fight cancer has proved more difficult than most people expected. Designing a cancer vaccine requires a deep understanding of the immune system’s intricacies—knowledge that has come about only in the past few years. In addition, cancer cells can flip chemical switches to subvert attacks by the immune system, adding a layer of difficulty to vaccine design.

To date, no cancer vaccine has been approved by the U.S. Food and Drug Administration. The vaccine against cervical cancer that’s been in the headlines is a conventional preventive vaccine that targets the virus that causes cervical cancer.

The only therapeutic cancer vaccine that’s come close to approval is a prostate cancer treatment called sipuleucel-T. In March, an FDA advisory panel gave sipuleucel-T the thumbs-up, but the agency decided to delay approval pending the completion of a large trial in men with prostate cancer.

“The reality is that [the field] has been and continues to be waiting for a clear clinical success,” says Drew Pardoll, professor of oncology at Johns Hopkins University in Baltimore.

Recent research has not only revealed the switches that tumor cells flip to defuse an attack from the immune system, but has also yielded possible drugs to counteract this ploy. Paired with vaccines, several of these new drugs appear to be able to unleash the potential of the vaccines to spur the immune system to attack cancer cells.

Many researchers say that these “combinatorial” therapies could be the way forward for cancer-vaccine research. “We can beat this disease with the immune system with the right kinds of combinatorial approaches,” Pardoll says.

Subterfuge and betrayal

In their housecleaning role, roving sentries of the immune system identify and destroy badly damaged cells in the body. But cancer cells, which by definition are damaged cells that grow and proliferate unchecked, are surprisingly crafty adversaries.

The immune system has control mechanisms to prevent immune cells from attacking the body’s healthy cells. As part of this control system, killer T cells, the immune system’s attack dogs, require multiple signals before they’ll swing into action.

First, they need immune cells called dendritic cells to chew up a sample of the target and present a piece to the killer T cell as an example of what to look for. Dendritic cells play a key role in activating an immune response—whether against a foreign microbe or a damaged body cell—so many of the most promising new cancer vaccines use dendritic cells to train the immune system to recognize tumor cells. Sipuleucel-T is one such product.

But to activate killer T cells, or killer Ts, so-called helper T cells must release chemical cues. Regulatory T cells (T-regs), yet another kind of cell, function as the brakes of the immune system by producing compounds that keep killer Ts in check.

Tumors manipulate these elaborate control mechanisms to fool the immune system into treating cancer cells like friends instead of foes, a phenomenon called tolerance. “This is the central mission of the field—to selectively break tolerance to these tumors,” Pardoll says.

For example, cancer cells emit a protein called vascular endothelial growth factor (VEGF), which triggers the creation of new blood vessels to feed the fast-growing tumor. Conveniently for the tumor, VEGF also stifles the maturation of dendritic cells. Keeping dendritic cells stuck in an immature state prevents them from performing their critical role of training and activating killer Ts. What’s more, these immature dendritic cells actually stimulate T-regs, which suppress the immune response even further. Dendritic-cell development is also hindered by other tumor compounds, including the immune-signaling molecules interleukin 6 and 10, a substance called transforming growth factor—beta, and the inflammation-related enzyme cyclooxygenase-2.

Cancer cells can also release chemical signals that recruit T-regs and draw them into the tumor. “We know that these T-regs are sitting in the cancer and actually deactivating the [killer] T cells,” says Elizabeth M. Jaffee of the Sidney Kimmel Cancer Center at Johns Hopkins.

Ironically, it’s often the immune system itself that pushes cancer cells to such nefarious lengths. Scientists have confirmed in recent years that a person’s immune system has an innate ability to detect and kill some precancerous cells.

However, sooner or later, one of these precancerous cells will mutate such that it begins producing some of the signaling molecules that protect it against attack. In the same way that the overuse of antibiotics drives the evolution of drug-resistant “superbugs,” the immune system applies an evolutionary pressure on precancerous cells that pushes them to develop defenses against it. The cell in which that pivotal defensive mutation occurs is then free to proliferate wildly and to develop into full-blown cancer.

“We’ve come to look at the development of cancer in a person as an evolutionary struggle between rapidly mutating cells and the immune system,” says Louis M. Weiner of the Fox Chase Cancer Center in Philadelphia.

Decloaking tumor cells

The latest strategy in cancer vaccines combines them with drugs that subvert these sophisticated defenses of tumors. By disabling the stop signals that cancer cells send to a person’s immune system, these combination therapies should enable vaccines to do their jobs and spur immune cells into action against tumors. Experiments in mice and early trials in cancer patients are beginning to show that scientists might finally be on the right track.

“There are [experimental] vaccines now that are going into patients that are so much more potent at breaking tolerance than has ever been seen in the vaccines from the previous era,” Pardoll says.

One promising strategy involves combining vaccines with drugs that block the action of a protein called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This substance sits on the surface of T cells, and when activated, suppresses killer Ts’ tumor-fighting activity. Blocking CTLA-4 can release this brake on the immune system.

A small trial in patients in the Netherlands combined a CTLA-4 blocker called ipilimumab with an experimental cancer vaccine called GVAX. At the 2007 conference of the American Society of Clinical Oncology in Chicago, Winald Gerritsen of the Free University Medical Center in Amsterdam and his colleagues announced that the combination treatment reduced blood concentrations of prostate-specific antigen, a protein produced in excess by abnormal prostate cells, in 5 of 6 prostate cancer patients.

Tests of the patients’ immune system activity showed that their killer Ts and dendritic cells had become activated, indicating that the drug had released the checks on these cells so that the vaccine could rally them to action. With so few people in the trial, the results are only provisional, but “you have to sit up and take notice,” Pardoll says.

“If you saw results like this in larger trials, it would be almost unprecedented,” says Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute in Bethesda, Md.

Studies of similar combination therapies in mice have produced even more dramatic results. A team led by James P. Allison of the Memorial Sloan-Kettering Cancer Center in New York City treated mice with skin cancer using a similar therapy of GVAX with a CTLA-4 blocker. The treatment eliminated tumors in more than 90 percent of the mice, the team reported in the July 2006 Journal of Clinical Investigation. The balance between the numbers of killer T cells and T-regs within the tumor clearly shifted in favor of killer Ts, showing that the combo therapy weakened the cancer’s defenses and released the brakes on the immune system.

Unfortunately, releasing these brakes can also have adverse effects. In the Netherlands study, for example, most of the patients developed significant loss of kidney and thyroid function as well as flulike symptoms, all presumably due to the patients’ immune systems attacking healthy cells in their bodies.

Another strategy involves pairing a vaccine with a compound that inhibits T-regs. Suppressing T-regs removes the brake on killer Ts, allowing them to mount an attack against the tumor. One particularly effective T-reg suppressor is the chemotherapy drug cyclophosphamide. François Martin and his colleagues at the French National Institute of Hygiene in Dijon showed in 2004 that giving rats with colon cancer cyclophosphamide along with a cancer vaccine enabled their immune systems to destroy the tumors, while the vaccine alone could not.

“Finding ways to reduce T-regs is one of the most promising things going on in the field,” says Jarrod Holmes of the Cancer Vaccine Development Lab in Bethesda, Md.

VEGF also provides a ripe target for drugs. Drugs that block VEGF allow dendritic cells to mature, thus improving the effectiveness of cancer vaccines, as Leisha A. Emens of the Johns Hopkins University School of Medicine and her colleagues report in the July 1 Clinical Cancer Research. The researchers found that a cancer vaccine for breast cancer shrank tumors in mice more quickly when given with a VEGF inhibitor called DC101. Suppressing T-regs by adding cyclophosphamide to the mix made the cancer-fighting effect of the combination even stronger.

Round peg, square hole

Although researchers in the field are optimistic, these combination vaccines are moving through the drug-development pipeline toward larger trials very slowly.

Because drugs are normally tested and approved one at a time, the industry is organized around single-drug development. This structural bias against multiagent therapies has hampered the development of these new vaccines, researchers say. Vaccines that are farthest along in the approval process, such as the prostate cancer treatment sipuleucel-T, generally aren’t combination therapies.

“I’m not saying that it’s anyone’s fault,” Jaffee says, “but unfortunately, the way our process for drug development is, it’s very slow if you want to get approval for more than one agent.”

Normally, each component of the treatment must make it through human trials on its own. And to pass the trials, a drug must be more than just safe; it must also be effective. Often, contend Jaffee and others, the components of a combination vaccine are effective at killing tumors only when used together, making it difficult to get a component approved on its own.

Scientists are afraid of trying combined vaccine-drug therapies until each component is FDA approved, Schlom says. A scientist who combines an unapproved drug with an experimental vaccine puts both compounds at risk of never reaching the market and the clinic. If early trials of the combo show toxic effects in people, it may be impossible to justify further trials of the compounds, even though the cause of the toxic effects—be it the drug, the vaccine, or the synergy of the two—may be unknown.

With these policy challenges, as well as formidable research obstacles, to overcome, the field certainly has a long way to go. But recent progress hints at the unique payoff that’s possible with cancer vaccines. “The future is very, very bright,” Pardoll says.

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