Drs. David McDermott began treating people with kidney cancer in the 1990s. At the time, he said the prognosis for most of his patients with advanced disease was frustratingly grim. “We had very few treatment options, and patients’ survival was a year or less,” he recalls. “Radiation and chemotherapy have been tried, but they have not worked.”
Things started to change when researchers discovered it kidney cancers They had a high degree of ‘angiogenesis’ compared to most other forms of cancer, which means that kidney tumors are rich in blood vessels. This insight supported the development of angiogenesis inhibitors, a type of drug that cuts off the blood supply to these tumors. “These drugs were very effective because of the biologics that cause most kidney cancers,” says McDermott, MD, professor of medicine at Harvard Medical School and a cancer specialist at Beth Israel Deaconess Medical Center in Boston. Life expectancy doubled – a huge leap forward, but it left plenty of room for further improvement.
A more significant breakthrough — some cancer researchers say has revolutionized the treatment of kidney cancer — arrived just a decade ago. “The big innovation that changed things was the immune checkpoint inhibitors,” McDermott says. Many cancers, including kidney cancers, have built-in defenses that allow them to fend off the attacks of the human immune system. Immune checkpoint inhibitors help thwart these defenses. “If you think of a tumor’s defense against an immune attack like barbed wire, then this class of immunomodulatory drugs is meant to cover the barbed wire and allow the immune system to do its job,” he explains.
Kidney cancers are among the 10 most common types of cancer in men and women: About 79,000 new cases will be diagnosed in 2022, according to the American Cancer Society. When cancer is first diagnosed, more than 20% of patients already have advanced disease, which means the cancer has spread outside the kidney. Even among those whose cancer is confined to the kidneys who undergo surgery, 30% will eventually develop metastatic disease.
Immune checkpoint inhibitors remain one of the Primary treatments for kidney cancerAnd recent advances in the science of these drugs are still a great story in therapeutic progress. But it’s not the whole story. Here, McDermott and other experts describe the current care landscape, including the latest innovations.
Unblock the immune system
Thirty years ago, American immunologist Jim Allison led a research effort that revealed the existence of immune checkpoints. Specifically, he and his colleagues found that a protein on the surface of the immune system’s T cells acts as a checkpoint, or suppression, to prevent the immune system’s excessive response.
Allison’s work led to the discovery that cancer cells take advantage of these checkpoints in ways that allow them to limit or evade the protections built into the human body. These ideas led to drugs that changed the face of cancer care, including kidney cancer. “Professor Jim Allison’s work opened up the field for immune checkpoint inhibitors and other immunotherapies, leading to the golden age of immunotherapy that we see now,” says Dr. Nizar Tanner, an oncologist and cancer researcher at the university. From the Texas MD Anderson Cancer Center in Houston. The U.S. Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor to treat kidney cancer in 2015. Since then, more of these drugs have received FDA approval. They target CTLA-4, PD-1 and PD-L1 proteins found in immune cells that can limit the immune system’s attacks against cancer cells.
Even among people without metastatic kidney cancer, Immune checkpoint inhibitors It is now being tested as a treatment after kidney surgery. “Patients with kidney cancer that is confined to an organ usually have a nephrectomy,” Tanner says, referring to surgery that involves nephrectomy. “Just last November, the US Food and Drug Administration approved pembrolizumab in patients at risk of relapse after nephrectomy.” The approval came after a clinical trial that showed patients treated with pembrolizumab were more likely to be disease-free two years after surgery than those who received a placebo.
While immune checkpoint inhibitors have begun as “second-line” treatments, to be used only after other treatments have failed, they are increasingly being used as first-line treatments. “This is probably the biggest innovation of the last five years,” McDermott says. He explains that one of the interesting things about immune checkpoint therapy is that some of the best-responding patients are those with the most aggressive tumors. “This is the opposite of what you might see with chemotherapy, where patients with slow-growing tumors benefit more,” he says. Why does this happen? One theory is that aggressive cancers may look very different from normal tissue, so the immune system, once it releases its brakes, is better able to locate and attack these tumors. Because some kidney cancers develop quickly, it is best to start immune checkpoint therapy as soon as possible. “By giving immunotherapy early, as the first line of treatment, more patients don’t die early,” he says.
Another advance in immunotherapy involves using combinations of these drugs — either together or with other kidney cancer drugs — rather than spreading them on their own. Currently, McDermott says, it is common practice to combine a single immune checkpoint inhibitor with an older class of kidney cancer drugs (angiogenesis inhibitors). “This is a fusion of the old first-line treatment – drugs that target blood vessels – with the new first-line treatment,” he says. “When put together, most of the benefits are additive, but in some patients it can also be synergistic.” In other words, the drugs may work better together than either when used independently.
While the use of two or more immune checkpoint inhibitors together is less common, some formulations are approved for use in both the United States and Europe. McDermott says he is a supporter of this approach despite the greater potential for adverse reactions. “Blocking two of these immune checkpoints instead of one can significantly increase the immune response to both the tumor and normal tissue,” he says. “So it seems to increase the chances of the disease remission, but it also increases the chances of sepsis.”
How much does the risk of toxicity increase? When taking an immune checkpoint inhibitor, it is estimated that approximately 1 in 10 patients have to stop treatment due to side effects, which can include joint pain, bowel dysfunction, and other debilitating symptoms. This rate doubles to 2 in 10 when a second immunotherapy is added. Even if treatment does not have to be discontinued, side effects tend to be more severe when a person takes multiple immunotherapies. “It’s really about the philosophy of appropriate treatment goals,” he says. “Most oncologists do not believe that kidney cancer is a curable disease.” As a result, he says, they tend to choose drug combinations with milder side effects and good near-term results. “I would argue that long-term results are better with a combination of immune checkpoint inhibitors, but comparative trials are warranted to formally resolve this important debate,” he says.
Other experts share his view that combinations of immunotherapies may offer the best chance of long-term survival. “If you look at median survival 10 years before approval of the first immune checkpoint inhibitor, clinical trials have reported an overall median survival of 20 to 30 months for patients with newly diagnosed metastatic cancer. Specialist at Memorial Sloan Kettering Cancer Center in New York City. Citing the latest research on combination therapies with immune checkpoint inhibitors, he says median survival is estimated to be fifty months or more for most patients. “This is nearly double what it was, and a much higher percentage of patients are able to achieve complete remission,” he says.
This last point points to a compelling area of kidney cancer research. Why do some patients respond well to current medications – in some cases, the cancer is removed – while others do not? Advances in tumor characterization and biomarkers for kidney cancer–an umbrella term for a cancer’s traits or characteristics–may help solve this puzzle.
Unmask the enemy
A major theme in cancer research – and not just in kidney cancers – is the recognition that the disease is highly variable. Voss says kidney cancer comes in different “flavors,” or molecular subtypes, that help experts understand how cancer develops and why it may respond to different types of treatment. By studying biomarkers of kidney cancer, he and other experts hope to be able to better predict which patients do best on specific drugs or drug combinations.
“Some tumors appear to be more dependent on altering metabolism in certain ways, while others are highly dependent on the tumor’s blood vessels,” he says. Understanding these types of differences and their therapeutic implications, as well as identifying ways to assess the presence of these differences in people with kidney cancer, is critical to improving outcomes. Scientists are studying how to better address these differences to “match people with appropriate treatment,” he says.
Kidney biomarkers and their subclassification can also help improve the science of targeted therapies (including Immunotherapy) for kidney cancer. “If you understand what is happening on the surface of cancer cells, you can provide more targeted therapies and achieve a much stronger immune response,” Voss says. For example, chimeric antigen receptors, or CARs, are molecularly modified proteins designed to bind to a cancer cell (but not healthy cells) and invoke an immune response. While these have been used successfully for other types of cancer, they have only recently made their way into clinical trials for kidney cancer. “The whole field is holding its breath because of these results, which we should have in the next year or two,” he says. This could provide another major leap forward in the treatment of kidney cancer.
More reasons for optimism
There is a lot going on in kidney cancer care. Another promising advance, McDermott says, includes a class of drugs known as hypoxia-inducible factor (HIF)-2α inhibitors. HIF-2α helps tumors develop new blood vessels, use nutrients more efficiently, and adapt in other ways that support their proliferation and survival. HIF inhibitors are medications that can block all of these alterations. “The early results of HIF-2α factors are encouraging,” he says. Meanwhile, he says several new immunotherapies and targeted therapies are in development as well.
With a view of 10,000 feet, it appears that the foundations have been laid – and in some cases, impressively built – treatment that will eventually lead to reliable remission for most people with advanced kidney cancer. Already, cancers that were once fatal are successfully treated. Looking to the future, the development of cancer subclassification and mapping of biomarkers should help ensure that patients are given the most effective drugs with the lowest risk of side effects. Given how dramatically the treatment picture has changed in just the past five or ten years, there is reason to expect more significant developments in the near future.
As MD Anderson’s Tanner says, “there is more hope than ever for patients for improved survival, and even complete and lasting recovery with the possibility of a cure.”
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