Coley’s experiments were the first forays into a field of cancer research known today as immunotherapy. Since his first experiments, the oncology world has mostly moved on to radiation and chemo treatments. But for more than a century, immunotherapy—which encompasses a range of treatments designed to supercharge or reprogram a patient’s immune system to kill cancer cells—has persisted, mostly around the margins of medicine. In the last few years, though, an explosion of tantalizing clinical results have reinvigorated the field and plunged investors and pharma execs into a spending spree.
Though he didn’t have the molecular tools to understand why it worked, Coley’s forced infections put the body’s immune system into overdrive, allowing it to take out cancer cells along the way. While the FDA doesn’t have a formal definition for more modern immunotherapies, in the last few years it has approved at least eight drugs that fit the bill, unleashing a flood of money to finance new clinical trials. (Patients had better come with floods of money too—prices can now routinely top six figures.)
But while the drugs are dramatically improving the odds of survival for some patients, much of the basic science is still poorly understood. And a growing number of researchers worry that the sprint to the clinic offers cancer patients more hype than hope.
Prasad has come to be regarded as a professional cancer care critic, thanks to his bellicose Twitter style and John Arnold Foundation-backed crusade against medical practices he says are based on belief, not scientific evidence. Using national cancer statistics and FDA approval records, Prasad recently estimated the portion of all patients dying from all types of cancer in America this year who might actually benefit from immunotherapy. The results were disappointing: not even 10 percent.
Now, that’s probably a bit of an understatement. Prasad was only looking at the most widely used class of immunotherapy drugs in a field that is rapidly expanding. Called checkpoint inhibitors, they work by disrupting the immune system’s natural mechanism for reining in T cells, blood-borne sentinels that bind and kill diseased cells throughout the body. The immune cells are turned off most of the time, thanks to proteins that latch on to a handful of receptors on their surface. But scientists designed antibodies to bind to those same receptors, knocking out the regulatory protein and keeping the cells permanently switched to attack mode.
The first checkpoint inhibitors just turned T cells on. But some of the newer ones can work more selectively, using the same principle to jam a signal that tumors use to evade T cells. So far, checkpoint inhibitors have shown near-miraculous results for a few rare, previously incurable cancers like Hodgkin’s lymphoma, renal cell carcinoma, and non-small cell lung cancer. The drugs are only approved to treat those conditions, leaving about two-thirds of terminal cancer patients without an approved immunotherapy option.
But Prasad says that isn’t stopping physicians from prescribing the drugs anyway.
“Hype has encouraged rampant off-label use of checkpoint inhibitors as a last-ditch effort,” he says—even for patients with tumors that show no evidence they’ll respond to the drugs. The antibodies are available off the shelf, but at a list price near $150,000 per year, it’s an investment Prasad says doctors shouldn’t encourage lightly. Especially when there’s no reliable way of predicting who will respond and who won’t. “This thwarts one of the goals of cancer care,” says Prasad. “When you run out of helpful responses, how do you help a patient navigate what it means to die well?”
After more than a decade stretching out the promise of checkpoint inhibitors, patients—and businesses—were ready for something new. And this year, they got it: CAR T cell therapy. The immunotherapy involves extracting a patient’s T cells and genetically rewiring them so they can more efficiently home in on tumors in the body—training a foot soldier as an assassin that can slip behind enemy lines.
In September, the FDA cleared the first CAR-T therapy—a treatment for children with advanced leukemia, developed by Novartis—which made history as the first-ever gene therapy approved for market. A month later the agency approved another live cell treatment, developed by Kite Pharma, for a form of adult lymphoma. In trials for the lymphoma drug, 50 percent of patients saw their cancer disappear completely, and stay gone.
Kite’s ascendance in particular is a stunning indicator of how much money CAR-T therapy has attracted, and how fast. The company staged a $128 million IPO in 2014—when it had only a single late-phase clinical trial to its name—and sold to Gilead Science in August for $11.9 billion. For some context, consider that when Pfizer bought cancer drugmaker Medivation for $14 billion last year—one of the biggest pharma deals of 2016—the company already had an FDA-approved blockbuster tumor-fighter on the market with $2 billion in annual sales, plus two late-stage candidates in the pipeline.
While Kite and Novartis were the only companies to actually launch products in 2017, more than 40 other pharma firms and startups are currently building pipelines. Chief rival Juno Therapeutics went public with a massive $265 million initial offering—the largest biotech IPO of 2014—before forming a $1 billion partnership with Celgene in 2015. In the last few years, at least half a dozen other companies have made similar up-front deals worth hundreds of millions.
These treatments will make up just a tiny slice of the $107 billion cancer drug market. Only about 600 people a year, for example, could benefit from Novartis’ flagship CAR-T therapy. But the company set the price for a full course of treatment at a whopping $475,000. So despite the small clientele, the potential payoff is huge—and the technology is attracting a lot of investor interest. “CAR-T venture financing is still a small piece of total venture funding in oncology, but given that these therapies are curative for a majority of patients that have received them in clinical trials, the investment would appear to be justified,” says Mandy Jackson, a managing editor for research firm Informa Pharma Intelligence.
Sometimes, the modified T cells go overboard, excreting huge quantities of molecules called cytokines that lead to severe fevers, low blood pressure, and difficulty breathing. In some patients it gets even worse. Sometimes the blood-brain barrier inexplicably breaks down—and the T cells and their cytokines get inside patients’ skulls. Last year, Juno pulled the plug on its lead clinical trial after five leukemia patients died from massive brain swelling. Other patients have died in CAR-T trials at the National Cancer Institute and the University of Pennsylvania.
Scientists don’t fully understand why some CAR-T patients experience cytokine storms and neurotoxicity and others come out cured. “It’s kind of like the equivalent of getting on a Wright Brother’s airplane as opposed to walking on a 747 today,” says Wendell Lim, a biophysical chemist and director of the UC San Francisco Center for Systems and Synthetic Biology. To go from bumping along at a few hundred feet to cruise control at Mach 0.85 will mean equipping T cells with cancer-sensing receptors that are more specific than the current offerings.
Take the two FDA-approved CAR-T cell therapies, he says. They both treat blood cancers in which immune responders called B cells become malignant and spread throughout the body. Doctors reprogram patients’ T cells to seek out a B cell receptor called CD-19. When they find it, they latch on and shoot it full of toxins. Thing is, the reprogrammed T cells can’t really tell the difference between cancerous B cells and normal ones. The therapy just takes them all out. Now, you can live without B cells if you receive antibody injections to compensate—so the treatment works out fine most of the time.
But solid tumors are trickier—they’re made up of a mix of cells with different genetic profiles. Scientists have to figure out which tumor cells matter to the growth of the cancer and which ones don’t. Then they have to design T cells with antigens that can target just those ones and nothing else. An ideal signature would involve two to three antigens that your assassin T cells can use to pinpoint the target with a bullet instead of a grenade.
Last year Lim launched a startup called Cell Design Labs to try to do just that, as well as creating a molecular on-off-switch to make treatments more controlled. Only if researchers can gain this type of precise command, says Lim, will CAR-T treatments become as safe and predictable as commercial airline flight.
The field has matured considerably since Coley first shot his dying patient full of a dangerous bacteria, crossed his fingers, and hoped for the best. Sure, the guy lived, even making a miraculous full recovery. But many after him didn’t. And that “fingers crossed” approach still lingers over immunotherapy today.
All these years later, the immune system remains a fickle ally in the war on cancer. Keeping the good guys from going double-agent is going to take a lot more science. But at least the revolution will be well-financed.
Continue at: https://www.wired.com/story/cancer-immunotherapy-has-arrived-but-not-for-everyone/
The text above is owned by the site above referred.
Here is only a small part of the article, for more please follow the link