Brain Tumor Researchers Let Slip the Immune Cells of War


by Hakon Heimer

May, 2005

The formation of a tumor in the brain is a special case: advances in treatment for cancer elsewhere in the body have proved ineffectual for the most serious brain tumors. Now, however, researchers are finding promise in treatments that call upon the human body's own immune system.

Brain tumors have a special place in the popular imagination as the epitome of the incurable disease. Although not all brain tumors are fatal and some are highly treatable, gliomas-tumors that arise from the glia, or supporting cells, of the nervous system-are justifiably feared. For people with high-grade glioma, also called glioblastoma multiforme, the average survival is just shy of a year, and very few patients live longer than two years. 
 

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A T cell, left, and larger dendritic cell are two componenets of the immunce system that may be able to battle brain tumors. David Scharf / SCIENCE PHOTO LIBRARY

Glioblastoma remains almost impossible to arrest or even to slow. The reasons are many, including the ability of glioblastoma cells to evade surgical resection by hiding among the healthy cells of the brain. This also prevents attacking the tumor cells with high doses of radiation or drugs that would kill brain cells.

Some researchers have therefore set their sights on the immune system, which can hunt out and destroy very specific target cells in the body. Many think the understanding of the immune system is reaching the point where it will soon be feasible to train immune cells to target brain tumor cells.

Learning about the Immune System


In the late 19th century, New York physician William B. Coley noted that bacterial infections appeared to reduce the size of some tumors. Though he misinterpreted this finding to mean that something in bacteria could combat cancer cells, Coley's subsequent experiments foreshadowed many later attempts to rouse the immune system against cancer. According to the modern-day theory of how immune-system surveillance works, based in part on the observation that immunocompromised AIDS patients begin to develop tumors, the immune system constantly detects and eliminates cells that have mutated and begun to multiply abnormally. Both major arms of the immune system are involved in this process.

The early response, or "innate," immune system is designed to rapidly detect and destroy or sequester foreign invaders in the body. Traveling about the body with generalized descriptions of intruders such as bacteria, fungi, or viruses, and with the ability to recognize and leave unharmed the body's own cells, innate immune system cells such as macrophages and natural killer cells and molecules such as cytokines and complement proteins mount early attacks.

They also alert the second arm of the immune defenses, one in which cancer researchers have placed great hope. The adaptive immune system trains an army of cells called lymphocytes to identify and destroy specific invaders. Special surveillance cells called antigen-presenting cells gobble up all or parts of intruders and travel to the lymph nodes. There, protein fragments of the intruders-termed antigens-are presented to T or B lymphocytes, which then travel back out into the body to search for and destroy cells bearing those markers.

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A brain tumor shrinks following injection with an experimental whole-cell tumor vaccine. This vaccine was a forerunner to those now being studied by Andrew Sloan and colleagues, who are now comparing ways of introducing tumor antigens to dendritic cells in cell cultures of human malignant glioma. Courtesy of Andrew Sloan

Given this complicated defense system, why do cancers form at all? In part, it may be because tumor cells are not "foreign-born" and can pass immune system scrutiny. However, because the brain is sequestered behind a protective "blood-brain barrier," surveillance cells circulating through the blood stream have never "seen" the brain tumor cells. Scientists have therefore reasoned that T lymphocytes, in particular, could be trained to attack cells carrying tumor antigens. Fortunately, unlike the surveillance cells, T cells do make their way to the brain.
Bringing T Cells to the Brain


Enlisting T cells against tumors has shown some success outside the brain. Researchers at the National Cancer Institute, led by Steven Rosenberg, first reported in 2002 that they had taken T cells from patients with the skin cancer melanoma, trained the cells against the cancer and reinfused them back into the body. In a small pilot trial, this approach reduced the presence of tumors in some patients whose disease had not responded to any other treatments, and in the April 2005 issue of the Journal of Clinical Oncology, the NCI researchers reported improvements in more than half the patients in a larger study.

Gregory Plautz and colleagues at the Cleveland Clinic in Ohio began similar work in patients with glioblas toma multiforme several years ago. They showed that they could safely harvest tumor cells from patients and use them as a vaccine to stimulate the production of tumor-targeted T cells in the patients' lymph nodes. These T cells were removed, multiplied in the laboratory, and then injected back into the patient.

Plautz's group completed Phase 1 (safety) trials for patients with both recurrent and newly diagnosed glioblastoma. "We found that it was both feasible and safe, but we also learned that it was difficult to prepare vaccine cells from every single patient," says Plautz. The researchers felt that it was necessary to refine the technique with some basic research before going back into the human trials.

In addition, Plautz notes, "The dose that Rosenberg and colleagues used is 10 or 15 times more than what we were using. The second thing that we've gone back to the lab to work on is how we more effectively amplify the number of T cells."

Dendritic Cells Train T Cells


Like many other researchers, Plautz is focusing especially on the most powerful surveillance/antigen-presenting cells, called dendritic cells. First discovered 30 years ago by immunologist Ralph Steinman and colleagues at Rockefeller University in New York City, dendritic cells can be filtered out of the blood and "fed" tumor cells in the laboratory. Pediatric oncologist Kavita Dhodapkar in Steinman's lab is currently looking at how best to prepare dendritic cells to present antigens to T cells, evaluating different ways of feeding them all or parts of brain tumor cells. In contrast, Plautz is evaluating a technique in which he fuses the live tumor cells with dendritic cells.

Once the dendritic cells have acquired, digested, and presented the tumor antigens on their surface, the next step is for them to give T cells a look at their quarry. This step can also be done in a laboratory dish, though Dhodapkar and colleagues favor putting the dendritic cells directly back into the body to activate the immune system, a strategy they think will lead to a long-term "immunologic memory." Since it has recently become possible to safely obtain both tumor cells and dendritic cells from children with brain tumors, Dhodapkar and her colleagues hope to begin testing this approach in the clinic in the very near future.

The immune system offers so many potential targets that the difficulty may be in choosing the most effective combination. Andrew Sloan and colleagues at the Moffitt Cancer Center in Tampa, Fla., took a step in that direction in a study reported in the November issue of Neurosurgery. The researchers compared, in cell cultures of human malignant glioma, the various ways of introducing tumor antigens to dendritic cells, ranging from feeding them only genetic material of tumor cells to the fusion technique. The two most effective approaches were fusion of the cells and feeding dying cancer cells to the dendritic cells, with dying cancer cells offering the most consistent response.

Combining Immunologic Approaches


Individual immune system molecules are also being employed to selectively kill tumor cells. Raj Puri and colleagues at the FDA's Center for Biologics Evaluation and Research discovered that the surface of glioblastoma multiforme cells is covered with large numbers of receptors-chemical docking ports-for the immune system molecules interleukin 4 and interleukin 13. Puri's group has since engineered complexes with these interleukins bound to a toxin. Hearkening back to Coley's work a century ago, the toxin is produced by bacteria.

"When the interleukin attaches to the receptor on a tumor cell, the whole complex goes inside the cell, where the toxin selectively kills the tumor cell," says Puri. Safety trials have been completed for both interleukins, and interleukin 13 bound to the toxin is now in the early stages of a Phase 3 (efficacy) trial to assess its effectiveness in "mopping" up the tumor cells that escape surgical removal of the main mass of the tumor.

Even if researchers can successfully and safely bring toxic interleukins and trained T cells to bear on brain tumors, these tactics may need to be combined with other immune strategies because cancers have mechanisms to interfere with the immune system. "High-grade malignant gliomas secrete immune system molecules such as cytokines and hormones that are very immunosuppressive," says Sloan.

Several approaches to enlisting other parts of the immune system have paid dividends during the past several decades. For example, the cytokine interleukin 2 can effectively treat certain melanomas and kidney cancers by stimulating a general increase in the production of T cells and B cells. Antibody approaches have also been successful. The drugs trastuzumab (sold in the United States as Herceptin) and rituximab (Rituxan) are actually antibodies designed to seek out antigens on the surface of certain specific tumor cell types and then interfere with tumor growth and attract other immune system molecules or cells to help kill the tumor cells.

Unleashing the immune system in the brain is not without risk-it is conceivable that misdirected T cells and other immune system warriors could attack brain cells by mistake, such as happens in multiple sclerosis. But as Sloan notes, "Imagine you had glioblastoma multiforme, and statistics said you had less than a year to live. If we could develop a vaccine that could cure it or keep it at bay for 5 to10 years, with a small chance of autoimmune disease, wouldn't you take that chance?"