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Target Tumors

Targeting tumors with a little help from the virus
Doctors have plenty of ways to kill cancer cells, but far fewer ways to target the attack precisely on tumor cells while sparing healthy ones. Targeting tissue matters: Indiscriminate cell killing is the chief cause of the dreadful side effects of conventional cancer treatment.

Sphere with web-like covering and attachments to surface This cervical cancer cell has an uneven surface with many cytoplasmic projections, which may enable it to move. Cancer cells are usually large and divide rapidly and chaotically. Photo: National Cancer Institute

Last week, scientists from the Albert Einstein College of Medicine in New York announced a new way to precisely target some of the common cancers that are caused by a virus. These include cervical cancer (caused by human papilloma virus), some liver cancers (caused by hepatitis B and C), and some lymphomas (caused by the Epstein-Barr virus). Over all, as many as 20 percent of cancers may be caused by viruses.

The system under study uses a highly selective molecule called an antibody to seek out and attach to molecules called antigens. The antibodies are joined to an iota of radioactive isotope; radiation emitted while the isotope decays kills cells in or near the tumor. Because the antigens are made only by certain viruses, and not by healthy cells, the treatment targets largely spares healthy tissue.

Arturo Casadevall, professor of microbiology and immunology at Einstein, and Ekaterina Dadachova, an associate professor of nuclear medicine, implanted cells from human cervical and liver cancers into lab mice, and found that the antibody-radiation combination stopped the cancer in its tracks. The treatment even caused some of the cervical cancers to shrink. Cancers in the control animals grew so fast that the animals had to be sacrificed within three weeks.

Graph indicates steady growth rates among untreated animals, decrease shown for tumor growth among treated animals
Antibodies linked to isotopes caused tumor volume to stabilize, while tumors grew fast in control animals. For some reason, antibody alone caused some reduction in tumor growth rate. Graph: PLoS One

Looking inside
Normally, antibodies of the immune system attack antigens located on the surface of cells. So how did the antibodies used in the study attach to viral proteins that are produced inside the cancer cells? "We think this works because any rapidly growing tumor has a large number of dead cells," Casadevall says. Even though the antigens are normally hidden inside the cells, where the antibody might not reach, "dying tumor cells leave antigens all over the place."

This means the treatment could even build on itself to become more effective, Casadevall speculates. "The second time you use it, you might get higher activity" if antibodies in the second treatment attach to the viral proteins spilled from cells that died during the previous treatment.

Although the treatment has the ability to specifically "find" tumor cells carrying the viral protein, it need not locate every one, Casadevall adds. The deadly radiation can travel up to one centimeter in the body, and the isotope can be chosen according to how much penetration is needed.

Cervical cancer in mice (caused by human papilloma virus)
Two pink, hairless mice, mouse on right has large, almond-shaped growth near right hip
On left, mouse treated with antibody-linked isotope; on right, a control mouse. The impaired immune system of these "nude" mice allows human cancer cells to be implanted for research. (Mice are shown 20 days after treatment.) Photos: PLoS One.

Turning aside side effects
Side effects are a bugaboo of cancer treatment, and it's always possible that the radiation would damage non-target cells. But Casadevall says the isotope chosen for the experiment, "Has a relatively short half-life, 17 hours, so one can imagine that after a few days it would all be gone. I suspect the antibody would ... eventually would be cleaned out by the immune system."

Furthermore, the antibody-antigen connection would concentrate delivery of the radiation on the tumor. That would spare most healthy tissue, which is often attacked by conventional cancer therapy.

Mice are not people, yet even if the radiation therapy works in people, Casadevall warns that it is likely to be used in combination with other treatments: "Cancer is so complicated, any successful therapy has to have multiple facets."

Let at hundred treatments bloom
Cancer is many diseases, not one, and the new approach illustrates how new treatments are exploiting our better understanding of cancer's development. "We thought lymphoma was one disease, for example, but it is multiple diseases, and some are caused by a virus," says Casadevall. "Numerous infectious diseases are increasingly associated with cancer, and if we can identify the infectious agent, that may give us the ability to target it."

Red blobs in untreated tumor show cancer advancing; blobs are largely absent in the treated tumor
On left, several cancer cells are evident in micrograph of untreated tumor. On right, tumor cells are rare, the indistinct border of the large one at bottom left of photo indicates that this tumor cell is dying. Images: PLoS One

The hardest part of the current study, he says, was selecting the best antibody, but the results make him hopeful that the tested antibodies will work against many virus-caused cervical and liver cancers. Ideally, each patient would not need a unique antibody.

A method for attacking cancer-causing viral proteins might eventually become a preventive treatment for the many people who carry hepatitis B or C but have not yet developed cancer. If conventional treatments fail to eliminate these viruses, Casadevall suggests that an antibody treatment may kill the infected cells before they can turn cancerous.

Such a treatment is a long way off, and the first patients for an experimental radiation-antibody treatment will be those who have "failed" conventional cancer treatment. Casadevall says Einstein has applied for a patent and licensed the technology to a company (which he would not name), but which is moving toward clinical trials. Casadevall is a consultant to this company.

Many new treatments take years to develop, but Casadevall says antibodies are generally benign, and radioactive isotopes have been used to treat cancer for 20 years. "There are patients who are desperate... The next step in the research is people, there really isn't another step."

- David Tenenbaum

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• Treating Cancer as an Infectious Disease-Viral Antigens as Novel Targets for Treatment and Potential Prevention of Tumors of Viral Etiology, Xing Guo Wang et al. (2007). PLoS ONE 2(10): e1114. doi:10.1371/journal.pone.0001114.

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