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Control of Cancer, Not Killing, Is Key to Treatment: Study

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By Sharon Kingman
Staff Writer

LONDON – Successful treatment of cancer depends not on killing tumor cells, but in beating them into submission using the immune system, a team of German researchers reported. They have identified a type of immune cell that can "re-educate" cancer cells, so that they enter prolonged periods of growth arrest.

Mice with tumors, which were treated with the immunotherapy, survived for many months in a healthy condition, compared with animals that were treated with a placebo.

Finances permitting, the scientists plan to develop a similar therapy that could be used to treat humans. The idea is to harvest a particular kind of white blood cell – T-helper cells – from patients, expose the cells to some of the immune system's chemical messenger molecules and then reinfuse the T-helper cells so that they can send harmful malignant cancer cells into a prolonged "sleep."

Martin Röcken, director of the department of dermatology of the University Medical Center Tübingen, told BioWorld International: "We are currently applying for a grant to fund a study of this therapy in patients with metastatic malignant melanoma, in which we would take the patient's T cells, prime them with a cancer peptide and then put them back in to the patient's body. But it would be possible to apply this strategy to any type of cancer."

Significantly, he added, the study challenges the long-held view that in order to treat cancer, the cells must be killed. "We hope this work will change that thinking. Researchers need to switch gears, from how to kill cancer to how to live with cancer, by educating the tumor using the immune system," he said. "This strategy is already successful in the treatment of AIDS."

Published in the Feb. 3, 2013, issue of Nature, the paper by Röcken and his collaborators showed, for the first time, that the immune system can control cancer by putting the tumor cells into a state of permanent growth arrest. The paper is titled, "T-helper-1-cell cytokines drive cancer into senescence."

For many decades, oncologists have directed their efforts at encouraging the immune system to kill cancer cells. But after toxic therapies that greatly reduce the presence of cancer in the body, cancers tend to regrow, sometimes very rapidly. Moreover, many patients with cancer have long periods in which their tumors do not grow, but there was little information about the mechanism responsible for that control. The immune system was a likely candidate, as sometimes cancers recur and metastasize following a period of immunosuppression.

To explore that aspect further, Röcken's group worked with a mouse model of cancer, in which cancers develop as a result of disturbed cell-cycle control. Like many other researchers, Röcken's group tried to kill the cancers. But instead of using killer cells, they used T-helper-1 cells. They chose those cells because they are the most aggressive in causing certain types of severe autoimmune disease.

When they infused the animals with T-helper-1 cells – which produce large amounts of interferon and tumor necrosis factor – that strategy doubled the life span of the animals. Yet they found that the T-helper-1 cells did not cause significant destruction of the cancer. When they studied the underlying mechanism, they found that the success of the therapy depended on the two cytokines, interferon and tumor necrosis factor.

"Most cancer immunotherapy treatments tried to date have been devised in order to encourage cytotoxic T cells or natural killer cells to kill the tumor cells," Röcken said. "But the cells we used were not capable of killing other cells – they were simply potent cytokine producers. We thought that they might produce inflammation, but much to our surprise, the cells did not invade the tumors; they simply surrounded the tumors – and the tumor cells stopped growing."

The effect lasted for weeks and sometimes for months.

Further experiments confirmed the findings. When cancer cells were isolated from a living animal and transplanted into mice with severe combined immunodeficiency, tumors grew very rapidly. But if the researchers infused growth-arrested, senescent cancer cells into those immunodeficient mice, the tumors remained senescent and did not grow.

In other experiments, the team showed that blocking cytokine signaling, or knocking out single molecules that were important for induction of growth arrest, negated the effects, so that the tumors grew like normal cancers.

Analysis of the signaling pathways showed that both interferon and tumor necrosis factor were required for the ability to send the cancer cells into permanent growth arrest.

"If only one was present, there was no real effect on this type of growth arrest," Röcken said.

As well as the proposed study to develop a treatment for cancer in humans, the team also plans to study the cancer cells that are in growth arrest, to find out more about how those differ from active cancer cells.

"We want to compare the genetic and protein profiles of the growing and the senescent cancer populations, to see at what level the growth arrest occurs," Röcken said. "Do they alter their genomes or their protein expression? This information will tell us more about how cancer cells can be re-educated."