TA New York City doctor named Dr. William Coley deliberately injected one patient with streptococcal bacteria at the close of the 19th Century. Coley wasn’t crazy. He hoped the bacterial infection would stimulate an immune response that would slow the spread of his patient’s cancer, which was inoperable. The experiment worked; the patient’s tumor shrank.
Coley, along with his collaborators in research, would continue to test the same treatments on over 1,000 patients. Although they had many failed attempts, there were also many successes, particularly for those with soft-tissue or bone cancers. Today, Coley is sometimes called the father of immunotherapy, which is a branch of medicine that attempts to activate or modify a person’s immune system in ways that help treat disease.
The most important area of immunotherapy research is still cancer. People suffering from bladder cancer will be the ones who benefit the most. “Bladder cancer is one of the cancers—along with melanoma, head and neck cancers, and kidney cancer—that are highly responsive to immunotherapy,” says Dr. Joaquin Bellmunt, director of the Bladder Cancer Program at the Harvard-affiliated Beth Israel Deaconess Medical Center in Boston.
Bellmunt claims that bladder cancer has a high rate of mutations in tumors. The human body tends to regard these sorts of mutations as “antigens”—meaning unwelcome threats that would normally instigate an immune response. However, cancer cells have features that allow their mutations to fly under the radar and evade the immune system’s antibodies. These defenses are countered by immunotherapies. In Bellmunt’s words, they “release the brakes” that prevent the immune system from launching a more formidable attack.
The emergence of immunotherapies has been a game-changer in the treatment and prevention of bladder cancer. But experts say that other recent advancements—including refinements in chemotherapies, radiation treatments, and surgery—are improving prognoses for people diagnosed with bladder cancer.
This section is for oncologists, bladder-cancer specialists, and others to discuss recent breakthroughs as well areas of research that might yield even greater benefits in the near future.
All the latest developments in immunotherapy
The use of immunotherapy to treat bladder cancer is nothing new. Since the 1970s, doctors following closely in Coley’s footsteps have given some bladder-cancer patients injections of bacillus Calmette–Guérin, or BCG, a bacteria that triggers a helpful kind of inflammation. “BCG has been standard treatment for non-invasive bladder cancers”—meaning early-stage cancers that have not spread beyond the bladder—“for the last 40 years,” Bellmunt says. “But when BCG failed, we had nothing left but cystectomy,” or bladder removal surgery.”
For patients with bladder cancer that has spread to other areas of their bodies, the situation is similar. If chemotherapy didn’t work, there were few alternatives. These therapies are not always effective, and the median survival times tend to be months rather than years.
People with bladder cancers of any stage, early or late-stage, are now able to use the latest immunotherapies. “2016 is the year the newer immunotherapies show up, and immediately some of these drugs were conditionally approved based on Phase 1 and 2 trials,” Bellmunt says.
Checkpoint inhibitors are a term that is used to describe many of the relatively recent immunotherapies. These drugs block or inhibit certain immune pathways, which could otherwise hinder a stronger immune response. Also known as anti-PD-1 or anti-PD-L1 drugs, these medications have “changed the treatment landscape” for people with advanced bladder cancers, according to a 2020 study in the New England Journal of Medicine (NEJM).
“With immunotherapy, if you actually look at the overall benefits, it’s pretty modest,” says Dr. Simon Crabb, a bladder-cancer specialist and associate professor in medical oncology at the University of Southampton in the U.K. To his point, that 2020 NEJMStudy found that immunotherapy prolonged the average survival time by seven months, as compared to standard chemotherapy. “But in a minority of patients, maybe 20% to 30%, you see exceptional responses,” Crabb says. “I’ve got people who’ve been on these drugs for four or five years.”
Figuring out why this happens—why some respond so much better than others to immunotherapy—is a focal point of current research efforts. “Something we’ve come to understand is that this isn’t one disease, it’s a subset of diseases that can be divided up based on genetic subtypes,” he explains. By mapping the genetic characteristics of different bladder cancers, experts hope to gain a -stronger understanding of how each responds to the current therapies—whether that involves a single immunotherapy medication or, as is becoming more common, immunotherapies mixed with chemotherapies or other drugs.
Immunotherapies can also be used in the earlier stages of bladder cancer. For example, there’s some hope that administering these drugs before bladder-removal surgery may be beneficial. “A long time ago, we found out that you can improve survival by giving chemotherapy before surgery, but it’s quite toxic,” says Dr. Yair Lotan, chief of urologic oncology at UT Southwestern Medical Center at Dallas. “Now we’re looking at using immunotherapy, or a combination of immunotherapy with targeted therapies, to avoid the need for systemic chemotherapy.”
Like all medications, immunotherapies have side effects. Side-effects can sometimes be unpredictable. “If the immune system is overstimulated, almost any organ system can be impacted,” Bellmunt says. Skin reactions—dry or itchy skin, rashes—are the most common complaint among people on these drugs. Inflammation of the thyroid, bowels or lungs occurs in a smaller proportion of patients (5% to 5%). The inflammation may cause diarrhea, breathlessness, or weight gain. “In rare cases we’ve even seen cardiovascular toxicity where patients developed myocarditis [heart inflammation] and died,” he says. Here again, researchers are working to better understand—and better predict-—how a person will respond to these treatments.
There is much more work to do, but these drugs can save lives. “Once you boost the immune system, there are patients whose immunologic memory prevents the tumor from recurring,” Bellmunt says. “These patients have a clear improvement in survival.”
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New Improvements In targeted therapies
The first line treatment for advanced bladder carcinomas is chemotherapy, despite all the advances and excitement surrounding immunotherapies. These are also areas where medical researchers have made progress.
Surface antigens are molecules that can trigger an immune response. They are found in bladder cancer tumor cells. This is why immunotherapies for bladder cancer can be very effective. Additionally, these antigens help to activate newer chemotherapy drugs known as antibody drug conjugates. “These drugs use these quite clever molecules that have an antibody on one end—something that will hopefully bind onto the antigens on cancer cells in a selective manner—and a chemotherapy agent on the other,” Crabb says.
He explains that conventional chemotherapy is unable to distinguish between cancerous cells from normal cells. Fast-growing cells that resemble cancer cells—such as those of the bone marrow, digestive tract, mouth, and scalp—typically draw friendly fire. Many people who have received chemotherapy experience severe side-effects such as fatigue, sores, nausea and hair loss. By selectively binding antigens from bladder cancer cells to their receptors, Antibody-drug Conjugates can help reduce collateral damage. “What it does is lock the chemotherapy onto this molecule that exists on top of the cancer cells, which hopefully spares the normal cells the direct exposure to chemotherapy,” Crabb says.
Bellmunt compares these drugs with microscopic taxis, which have a bomb in the back seat. “The taxi drives to the cancer cell, which internalizes it, and then it releases the bomb,” he says. “This is a new way of delivering chemotherapy that helps avoid side effects, and some trials have also shown a survival advantage compared to standard chemotherapy.” Right now, he says these drugs are used as a “third-line” treatment, or only in cases where standard chemotherapy and immunotherapy fail. But there’s hope that improvements in these drugs may soon push them higher up in the pecking order.
Antibody-drug conjugates are just one of several new “targeted” treatments for bladder cancer. A tyrosinekinase inhibit is another type of drug. “This is a drug that’s able to switch off a genomic trigger identified in the tumor,” Bellmunt explains. It is beneficial to switch off the trigger as it could be contributing to tumor growth and progression in some cases.
Researchers are currently looking into tyrosine-kinase inhibitors, and other precision drugs that can be used alongside immunotherapy or chemotherapy treatments. In the future, these drugs might be combined in order to bring about treatment breakthroughs. “We all hope that the right combination might change the future,” Bellmunt adds.
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What’s next in bladder-Cancer treatment
While the advancements described here are most notable, there are still many others.
New imaging technologies may make it possible to more precisely treat radiation. The area of genetic sequencing is also very active in research. “We’re getting better at identifying biomarkers of the disease that allow us to tailor our approaches,” Lotan says. “In just the last three or four years, we’ve moved forward in identifying underlying signatures of cancers and gene expressions that can help us personalize treatment options.”
Lotan says that many people in the field of bladder cancer screening are hopeful for accurate protocols. “From a detection standpoint, there hasn’t been any major advancement,” he says. “Newer detection methods use panels of RNA or DNA, which are more sophisticated, but so far we have not done the large scale studies needed to demonstrate clinical utility.” Those trials involve thousands of people and “a lot of money,” he adds, and will hopefully happen soon.
“It may be possible to use urine as a screening approach, and there’s quite a lot of work going on in that area,” Crabb adds. He’s optimistic this work will eventually bear fruit. “I think urine screening is the way forward,” he says. “It’s all well and good to develop these expensive new treatments, but prevention, or at least early detection, would be better.”
In the past, cancer specialists hoped that one cure would be all-encompassing and eradicate all forms of cancer. As they have gained more knowledge about the disease, these hopes are now fading. Many today recognize that the disease is far too complex to be treated with one solution. Therefore, there will always be many options for treatment. The good news for people with bladder cancer is that each new year seems to yield meaningful strides in medical science’s ability to fight the disease. Today’s picture is vastly different from it was ten or five years ago. Bladder cancer patients are now living longer with less side effects and suffering from less severe symptoms than ever. There’s reason to expect more improvements in the near future.
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