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New drugs harness the body's own cancer-fighting abilities

Immunotherapy drugs boast greater efficacy with fewer side effects

Merck's research facility in the U.S. state of Massachusetts

OSAKA -- A new class of drugs known as immune checkpoint inhibitors could drastically change the way cancer is treated. Rather than attack cancer cells directly, like conventional drugs, these new treatments work by unleashing the cancer-killing ability of the body's immune system.

Prices of immune checkpoint inhibitors, such as Opdivo, remain extremely high. But their potential for fighting -- or even eliminating -- cancer is garnering worldwide attention.

Junzo Hamanishi, an assistant professor at Kyoto University, says he has obtained remarkable results treating patients with Opdivo. "In some cases, patients who hadn't responded to other cancer drugs were completely cured," he said.

One problem with conventional anti-cancer drugs is resistance. Using the same drug for an extended period of time can cause the genetic makeup of cancer cells to change, rendering the treatment less effective. This problem reportedly does not occur with Opdivo because it operates under an entirely different mechanism.

Traditionally, the development of anti-cancer drugs has focused on finding substances that kill cancer cells directly. The first anti-cancer drug was created around 1950 from research on toxic gases. More sophisticated treatments followed, but they all killed cancer in basically the same way, by impeding DNA synthesis to prevent the cells from propagating. Unfortunately, these drugs also damaged healthy cells, causing numerous side effects.

Big steps

The start of the 21st century saw two major innovations. The first was molecularly targeted drugs, which attack only cancer cells. These drugs operate by interfering with the workings of molecules involved in propagation that appear on the cell surface. The result: fewer side effects and improved treatment rates. The downside is that these drugs are only effective for cancer patients with specific types of genetic disorders and cancer cells can develop a resistance to them.

Then came immune checkpoint inhibitors like Opdivo.

These drugs restore the offensive capabilities of the immune system that cancer cells try to neutralize. "The thinking was exactly opposite that of earlier treatment methods," said Tasuku Honjo, a visiting professor at Kyoto University. Honjo is a pioneer in the field of immune checkpoint inhibitors -- his work helped lead to the development of Opdivo.

Efforts to use the workings of the immune system to treat cancer have been around for decades. For example, the Maruyama vaccine and treatment methods using the tuberculosis vaccine BCG were developed in the 1970s. Later, other vaccines and treatment methods emerged, but, unlike today's treatments, the efficacy of most of these could not be scientifically verified.

Cancer occurs as a result of damage to the genes of normal cells. Every day, thousands of cells in the human body turn cancerous. What prevents them from developing into a life-threatening condition is the action of the immune system. When dendritic cells, which act as sentinels, detect a foreign substance in the body, they give the command for T cells and other immune cells to go on the attack and eliminate the invader.

But cancer cells are sometimes able to shut down this attack.

Break the breaks

The key to this process is a type of protein known as immune checkpoint molecules, which are found on the surface of T cells -- Honjo discovered one of these proteins, PD-1, in 1992. Once a cancer cell reaches a certain stage of growth, it develops a different protein, called PD-L1, on its surface. This protein binds with the PD-1 of a T cell, rendering that cell impotent. Opdivo works by breaking this bond and restoring the T cell's ability to attack.

Another molecule with a similar action is CTLA-4, whose function was elucidated in the 1990s by a group led by James Allison of the University of Texas. When dendritic cells give commands to attack cancer cells, CTLA-4 on the surface of the T cells intercepts the message, defusing the attack. In 2011, U.S. pharmaceutical company Bristol-Myers Squibb developed Yervoy to neutralizes this action.

Opdivo and Yervoy have produced better results in treating malignant melanoma, a type of skin cancer that conventional cancer drugs have not been very effective against. Both drugs reportedly caused the cancer to shrink in 20-30% of patients. In Japan, Opdivo has also been approved for treating some lung and kidney cancers.

Meanwhile, drugmakers like Merck of the U.S., Switzerland's Roche Holding and AstraZeneca of the U.K. are continuing to develop new immune checkpoint inhibitors. Merck's Keytruda was approved by Japan's health ministry in September and is expected go on sale in the country shortly. Like Opdivo, Keytruda interferes the bonding of PD-L1 with PD-1.

Pros and cons

Because molecularly targeted drugs target specific molecules on the surface of a cancer cell, different drugs are needed to treat different types. Because the immune system uses basically the same mechanism to eliminate cancer regardless of type, immune checkpoint inhibitors are reportedly effective against a wide range of cancers. Honjo's hope is that "within a decade, we might be able to conquer cancer."

Both Honjo and Allison have won international recognition for their work, and each has been touted as a likely candidate for the Nobel Prize in Physiology or Medicine.

But while immune checkpoint inhibitors promise to turn immunotherapy into a powerful fourth weapon in the fight against cancer -- joining surgery, chemotherapy and radiotherapy -- there are potential downsides.

For example, while side effects are rare, there is the risk of patients' own defenses making them seriously ill. Once the brakes are taken off, the immune system can run wild, attacking even healthy tissues and cells.

Cost is another issue. Treatment with either Opdivo or Yervoy costs several million yen and in some cases can top 10 million yen ($87,900). Research into methods for determining which patients will be most receptive to treatment is vital in order to keep costs down and avoid administering the drugs in vain.

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