Patients with a type of liver cancer known as hepatocellular carcinoma (HCC) often face an anxious wait after their tumor is removed. In nearly half of these people, the cancer will come back within 2 years of surgery or treatment that destroys their tumors with heat. Researchers have not identified any therapy that can prevent it from coming back.
That could change thanks to a class of drugs once seen as a failed revolution in cancer treatment. Angiogenesis inhibitors, which strangle tumors by cutting off their blood supply, never lived up to expectations when they reached clinical trials more than two decades ago. But now they’re getting a boost from a new set of drugs with a more impressive track record: checkpoint inhibitors, which release immune system T cells to attack tumors. At the American Association for Cancer Research (AACR) meeting last month, researchers presented evidence that the combination of an angiogenesis inhibitor and a checkpoint inhibitor delayed the recurrence in patients with HCC, a first for this type of cancer.
If the duo receives US Food and Drug Administration (FDA) approval, it will be the eighth pairing of OK drug types in the past 4 years. More than 200 clinical trials are currently testing this approach in various types of cancers, spurred by evidence that angiogenesis inhibitors help cancer-fighting T cells penetrate deep into tumors. “There’s a very clear rationale” for combining these two classes of drugs, says Robert Kerbel, a tumor immunologist at the University of Toronto.
This resurgence of angiogenesis inhibitors comes after astronomical expectations for the drugs were dashed in the late 1990s. Their premise was compelling. Tumors, hungry for oxygen and nutrients, should stimulate new blood vessels to grow and grow towards them; by preventing the formation of these vessels, angiogenesis inhibitors should starve tumors and slow their growth. But the drugs fell flat for a variety of reasons, including tumors becoming resistant or using other mechanisms to obtain blood. “It was an almighty crash” when the drugs didn’t work, says Francesco Pezzella, a tumor pathologist at the University of Oxford, whose team found that tumors can commandeer existing vessels instead of existing ones. develop new ones.
Still, angiogenesis inhibitors have had some success. The monoclonal antibody bevacizumab gained regulatory approval in 2004 for patients with advanced colon cancer, and more than a dozen other angiogenesis inhibitors have since joined the antitumor arsenal. But on their own, angiogenesis inhibitors usually add only a few months to a patient’s life. They “are very good at controlling disease, but by themselves they are not curative,” says medical oncologist Brian Rini of Vanderbilt University Medical Center.
Scientists constantly combine approved cancer drugs to test whether they work better together, but a phenomenon discovered more than 25 years ago may explain why the checkpoint inhibitor-angiogenesis inhibitor partnership is productive. The blood vessels inside a tumor are a mess – swollen, twisted and leaky. In the late 1990s, Rakesh Jain, a tumor biologist at Harvard Medical School (HMS), noticed that angiogenesis inhibitors had a surprising effect on tumors. The drugs “normalized” the vessels, causing them to narrow, straighten and become less porous. “What I saw was that the blood vessels (inside tumors) were getting better,” says Jain, who published his “vascular normalization” hypothesis in 2001. Although controversial at first, the explanation is now widely accepted, says Anette Magnussen, a cancer biologist at Oxford. .
Abnormal blood vessels leave inside an oxygen-poor tumor, inhibiting any T cells that enter to attack the tumor cells. This disables checkpoint inhibitors, which work by preventing cancer cells from flipping inhibitory switches on T cells. By restoring normal circulation to the tumor, angiogenesis inhibitors can reverse immunosuppressive conditions and allow Tumor-targeting T cells to pounce. Jain says normalizing tumor vessels may provide another benefit: stopping metastasis, the spread of tumor cells to other parts of the body. A tumor deprived of oxygen “is like a wounded tiger,” he says. It is more dangerous in this state because it tends to release cells which can move and establish new tumors elsewhere.
To date, dozens of clinical trials have evaluated checkpoint inhibitor-angiogenesis inhibitor combos. Some have proven to be toxic, and others have failed. However, the studies have also led the FDA to approve new therapies for types of liver, kidney, lung, and endometrial cancers. Drug combinations are not curative, but they do inhibit tumor growth. And some prolong the life of patients by several months compared to angiogenesis inhibitors alone.
The trials also revealed other promising results, including those for HCC, which liver surgeon Pierce Chow from Duke-NUS Medical School in Singapore presented at the AACR meeting. In a phase 3 trial, he found, a combination of bevacizumab and the checkpoint inhibitor atezolizumab reduced the odds of tumors coming back after surgery or heat treatment by 28 percent in patients whose disease was diagnosed early. Researchers are still following patients to determine if these benefits persist and if the combination increases survival.
Scientists don’t just mix and match existing options. At least one startup, DynamiCure, is looking to develop new angiogenesis-thwarting drugs that are safer and can be paired with checkpoint inhibitors. The company has already started a clinical trial of an antibody that stimulates vessel normalization. “When new businesses are created, that tells you the field isn’t dead, it’s thriving,” says Jain.
However, the strategy of combining the two types of drugs faces many challenges. For one thing, most angiogenesis inhibitors directly or indirectly interfere with vascular endothelial growth factor (VEGF), a molecule that induces blood vessel growth. However, normal tissues also need VEGF, and the drugs can cause side effects such as bleeding, high blood pressure, and strokes.
Beyond side effects, researchers need better ways to determine whether tumors respond to drug duos, Magnussen says. “The challenge for using this (strategy) in humans is how to monitor blood vessel normalization in a cost-effective and rapid manner.”
HMS cancer biologist Dan Duda fears researchers and pharmaceutical companies are rushing drug combinations into trials without considering the type of cancer and variables such as timing and timing of treatment. “We’re making the same mistakes we made the first time around” with angiogenesis inhibitors, he says, adding, “We should take our time and think a little bit.”