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Opdivo is a highly effective but extremely expensive cancer treatment drug.

Opdivo is a highly effective but extremely expensive cancer treatment drug.

Immunotherapy opens a fourth front in the war against cancer, following surgery, chemotherapy, and radiotherapy.

One area of promise is checkpoint inhibitor therapy, which short-circuits a defensive strategy cancers use to avoid attack by the immune system. Unfortunately, existing checkpoint inhibitors, like Opdivo, are extremely expensive.

But work is underway on compounds that can be used in combination with checkpoint inhibitors to boost their efficacy and, by doing so, reduce the amounts of these costly drugs that need to be administered.

That is good news for patients and medical insurance systems alike.

Consider the costs facing Japan. The Fiscal System Council, an advisory panel to Japan’s finance minister, brought up the topic of the cost of Opdivo in April. It estimated that treating 50,000 patients a year with this cancer drug would add ¥1.75 trillion ($16.9 billion) to the nation’s medical expenses for the medicine alone. The health ministry has decided to lower the government-sanctioned price of Opdivo next fiscal year, which starts in April.

Research teams at Osaka University and Keio University are investigating two different combination therapies that have demonstrated, in animal experiments, the ability to boost the efficacy of checkpoint inhibitors. The Osaka team is using fragments of the Sendai virus, while the Keio researchers are experimenting with statins. Their overall strategies, however, are the same: enhance the ability of the T cells of the immune system to attack cancer cells.

Both therapies are designed to be used in combination with checkpoint inhibitors such as Opdivo, which work by blocking a cell-surface receptor known as PD-1, short for programmed cell death protein 1.

Cancer cells avoid attack from T cells by targeting PD-1, putting a brake on the cells. Drugs such as Opdivo block this action, effectively taking the brakes off the T cells so they can continue to attack the cancer cells.

The Osaka University team, led by Yasufumi Kaneda, is investigating how it can take advantage of the way the Sendai virus activates the immune system. When harmless fragments of the virus are injected in the body, the immune system mistakes the fragments for a pathogen, sounding the alarm and mustering T cells to the attack.

In experiments using mice with malignant melanoma, the team found that the tumor mass shrank by at least two-thirds after 30 days of combination therapy, a better result than treating the mice with anti-PD-1 antibodies alone.

Kaneda’s team hopes to begin human clinical trials of this cancer combination therapy in fiscal 2017.

REGULATING THE REGULATORS
Meanwhile, the Keio University team, under Yutaka Kawakami, is studying a combination therapy that uses statins, a class of compounds normally used to treat high blood cholesterol.

The immune system has a subclass of T cells known as regulatory T cells, whose main job is to modulate the immune system so it does not attack the body’s own cells, as happens in autoimmune diseases.

The problem is that the regulatory T cells can do their job so well that they end up protecting cancer cells, too.

Statins work to suppress the action of these regulatory T cells, effectively giving the immune system carte blanche to attack cancer.

Kawakami’s team transplanted colorectal cancer cells into mice and then treated the animals with a combination of statins and anti-PD-1 antibodies. They found that the cancer cells grew less with this therapy than with anti-PD-1 antibodies alone.

Since some cancer patients also take statins for high cholesterol, the team plans to analyze past data to see if the relationship holds in humans as well. That could help shed light on the mechanism of action and open the door to drug discovery.

Besides their high cost, checkpoint inhibitors have another problem: They do not work on everybody. For example, only around 30 percent of patients respond to treatment with Opdivo alone. Drug companies around the world are thus working to develop other checkpoint inhibitors and explore their potential for use in combination with other cancer drugs.

The problem is that the regulatory T cells can do their job so well that they end up protecting cancer cells, too.