Study Shows “Living Drug” Can Provide a Lasting Cure for Cancer
Doug Olson was 49 when he was diagnosed with chronic lymphocytic leukemia, a blood cancer that strikes 21,000 Americans annually. Although the disease kills most patients within a decade, Olson’s case progressed more slowly, and courses of mild chemotherapy kept him healthy for 13 years. Then, when he was 62, the medication stopped working. The cancer had mutated, his doctor explained, becoming resistant to standard remedies. Harsher forms of chemo might buy him a few months, but their side effects would be debilitating. It was time to consider the treatment of last resort: a bone-marrow transplant.
Olson, a scientist who developed blood-testing instruments, knew the odds. There was only a 50 percent chance that a transplant would cure him. There was a 20 percent chance that the agonizing procedure—which involves destroying the patient’s marrow with chemo and radiation, then infusing his blood with donated stem cells—would kill him. If he survived, he would face the danger of graft-versus-host disease, in which the donor’s cells attack the recipient’s tissues. To prevent it, he would have to take immunosuppressant drugs, increasing the risk of infections. He could end up with pneumonia if one of his three grandchildren caught a sniffle. “I was being pushed into a corner,” Olson recalls, “with very little room to move.”
Soon afterward, however, his doctor revealed a possible escape route. He and some colleagues at the University of Pennsylvania’s Abramson Cancer Center were starting a clinical trial, he said, and Olson—still mostly symptom-free—might be a good candidate. The experimental treatment, known as CAR-T therapy, would use genetic engineering to turn his T lymphocytes (immune cells that guard against viruses and other pathogens) into a weapon against cancer.
In September 2010, technicians took some of Olson’s T cells to a laboratory, where they were programmed with new molecular marching orders and coaxed to multiply into an army of millions. When they were ready, a nurse inserted a catheter into his neck. At the turn of a valve, his soldiers returned home, ready to do battle.
“I felt like I’d won the lottery,” Olson says. But he was only the second person in the world to receive this “living drug,” as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
Three weeks later, Olson was slammed with a 102-degree fever, nausea, and chills. The treatment had triggered two dangerous complications: cytokine release syndrome, in which immune chemicals inflame the patient’s tissues, and tumor lysis syndrome, in which toxins from dying cancer cells overwhelm the kidneys. But the crisis passed quickly, and the CAR-T cells fought on. A month after the infusion, the doctor delivered astounding news: “We can’t find any cancer in your body.”
“I felt like I’d won the lottery,” Olson says. But he was only the second person in the world to receive this “living drug,” as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
An Unexpected Cure
In February 2022, the same cancer researchers reported a remarkable milestone: the trial’s first two patients had survived for more than a decade. Although Olson’s predecessor—a retired corrections officer named Bill Ludwig—died of COVID-19 complications in early 2021, both men had remained cancer-free. And the modified immune cells continued to patrol their territory, ready to kill suspected tumor cells the moment they arose.
“We can now conclude that CAR-T cells can actually cure patients with leukemia,” University of Pennsylvania immunologist Carl June, who spearheaded the development of the technique, told reporters. “We thought the cells would be gone in a month or two. The fact that they’ve survived 10 years is a major surprise.”
Even before the announcement, it was clear that CAR-T therapy could win a lasting reprieve for many patients with cancers that were once a death sentence. Since the Food and Drug Administration approved June’s version (marketed as Kymriah) in 2017, the agency has greenlighted five more such treatments for various types of leukemia, lymphoma, and myeloma. “Every single day, I take care of patients who would previously have been told they had no options,” says Rayne Rouce, a pediatric hematologist/oncologist at Texas Children’s Cancer Center. “Now we not only have a treatment option for those patients, but one that could potentially be the last therapy for their cancer that they’ll ever have to receive.”
Immunologist Carl June, middle, spearheaded development of the CAR-T therapy that gave patients Bill Ludwig, left, and Doug Olson, right, a lengthy reprieve on their terminal cancer diagnoses.
Penn Medicine
Yet the CAR-T approach doesn’t help everyone. So far, it has only shown success for blood cancers—and for those, the overall remission rate is 30 to 40 percent. “When it works, it works extraordinarily well,” says Olson’s former doctor, David Porter, director of Penn’s blood and bone marrow transplant program. “It’s important to know why it works, but it’s equally important to know why it doesn’t—and how we can fix that.”
The team’s study, published in the journal Nature, offers a wealth of data on what worked for these two patients. It may also hold clues for how to make the therapy effective for more people.
Building a Better T Cell
Carl June didn’t set out to cure cancer, but his serendipitous career path—and a personal tragedy—helped him achieve insights that had eluded other researchers. In 1971, hoping to avoid combat in Vietnam, he applied to the U.S. Naval Academy in Annapolis, Maryland. June showed a knack for biology, so the Navy sent him on to Baylor College of Medicine. He fell in love with immunology during a fellowship researching malaria vaccines in Switzerland. Later, the Navy deployed him to the Fred Hutchinson Cancer Research Center in Seattle to study bone marrow transplantation.
There, June became part of the first research team to learn how to culture T cells efficiently in a lab. After moving on to the National Naval Medical Center in the ’80s, he used that knowledge to combat the newly emerging AIDS epidemic. HIV, the virus that causes the disease, invades T cells and eventually destroys them. June and his post-doc Bruce Levine developed a method to restore patients’ depleted cell populations, using tiny magnetic beads to deliver growth-stimulating proteins. Infused into the body, the new T cells effectively boosted immune function.
In 1999, after leaving the Navy, June joined the University of Pennsylvania. His wife, who’d been diagnosed with ovarian cancer, died two years later, leaving three young children. “I had not known what it was like to be on the other side of the bed,” he recalls. Watching her suffer through grueling but futile chemotherapy, followed by an unsuccessful bone-marrow transplant, he resolved to focus on finding better cancer treatments. He started with leukemia—a family of diseases in which mutant white blood cells proliferate in the marrow.
Cancer is highly skilled at slipping through the immune system’s defenses. T cells, for example, detect pathogens by latching onto them with receptors designed to recognize foreign proteins. Leukemia cells evade detection, in part, by masquerading as normal white blood cells—that is, as part of the immune system itself.
June planned to use a viral vector no one had tried before: HIV.
To June, chimeric antigen receptor (CAR) T cells looked like a promising tool for unmasking and destroying the impostors. Developed in the early ’90s, these cells could be programmed to identify a target protein, and to kill any pathogen that displayed it. To do the programming, you spliced together snippets of DNA and inserted them into a disabled virus. Next, you removed some of the patient’s T cells and infected them with the virus, which genetically hijacked its new hosts—instructing them to find and slay the patient’s particular type of cancer cells. When the T cells multiplied, their descendants carried the new genetic code. You then infused those modified cells into the patient, where they went to war against their designated enemy.
Or that’s what happened in theory. Many scientists had tried to develop therapies using CAR-T cells, but none had succeeded. Although the technique worked in lab animals, the cells either died out or lost their potency in humans.
But June had the advantage of his years nurturing T cells for AIDS patients, as well as the technology he’d developed with Levine (who’d followed him to Penn with other team members). He also planned to use a viral vector no one had tried before: HIV, which had evolved to thrive in human T cells and could be altered to avoid causing disease. By the summer of 2010, he was ready to test CAR-T therapy against chronic lymphocytic leukemia (CLL), the most common form of the disease in adults.
Three patients signed up for the trial, including Doug Olson and Bill Ludwig. A portion of each man’s T cells were reprogrammed to detect a protein found only on B lymphocytes, the type of white blood cells affected by CLL. Their genetic instructions ordered them to destroy any cell carrying the protein, known as CD19, and to multiply whenever they encountered one. This meant the patients would forfeit all their B cells, not just cancerous ones—but regular injections of gamma globulins (a cocktail of antibodies) would make up for the loss.
After being infused with the CAR-T cells, all three men suffered high fevers and potentially life-threatening inflammation, but all pulled through without lasting damage. The third patient experienced a partial remission and survived for eight months. Olson and Ludwig were cured.
Learning What Works
Since those first infusions, researchers have developed reliable ways to prevent or treat the side effects of CAR-T therapy, greatly reducing its risks. They’ve also been experimenting with combination therapies—pairing CAR-T with chemo, cancer vaccines, and immunotherapy drugs called checkpoint inhibitors—to improve its success rate. But CAR-T cells are still ineffective for at least 60 percent of blood cancer patients. And they remain in the experimental stage for solid tumors (including pancreatic cancer, mesothelioma, and glioblastoma), whose greater complexity make them harder to attack.
The new Nature study offers clues that could fuel further advances. The Penn team “profiled these cells at a level where we can almost say, ‘These are the characteristics that a T cell would need to survive 10 years,’” says Rouce, the physician at Texas Children’s Cancer Center.
One surprising finding involves how CAR-T cells change in the body over time. At first, those that Olson and Ludwig received showed the hallmarks of “killer” T-cells (also known as CD8 cells)—highly active lymphocytes bent on exterminating every tumor cell in sight. After several months, however, the population shifted toward “helper” T-cells (or CD4s), which aid in forming long-term immune memory but are normally incapable of direct aggression. Over the years, the numbers swung back and forth, until only helper cells remained. Those cells showed markers suggesting they were too exhausted to function—but in the lab, they were able not only to recognize but to destroy cancer cells.
June and his team suspect that those tired-looking helper cells had enough oomph to kill off any B cells Olson and Ludwig made, keeping the pair’s cancers permanently at bay. If so, that could prompt new approaches to selecting cells for CAR-T therapy. Maybe starting with a mix of cell types—not only CD8s, but CD4s and other varieties—would work better than using CD8s alone. Or perhaps inducing changes in cell populations at different times would help.
Another potential avenue for improvement is starting with healthier cells. Evidence from this and other trials hints that patients whose T cells are more robust to begin with respond better when their cells are used in CAR-T therapy. The Penn team recently completed a clinical trial in which CLL patients were treated with ibrutinib—a drug that enhances T-cell function—before their CAR-T cells were manufactured. The response rate, says David Porter, was “very high,” with most patients remaining cancer-free a year after being infused with the souped-up cells.
Such approaches, he adds, are essential to achieving the next phase in CAR-T therapy: “Getting it to work not just in more people, but in everybody.”
Doug Olson enjoys nature - and having a future.
Penn Medicine
To grasp what that could mean, it helps to talk with Doug Olson, who’s now 75. In the years since his infusion, he has watched his four children forge careers, and his grandkids reach their teens. He has built a business and enjoyed the rewards of semi-retirement. He’s done volunteer and advocacy work for cancer patients, run half-marathons, sailed the Caribbean, and ridden his bike along the sun-dappled roads of Silicon Valley, his current home.
And in his spare moments, he has just sat there feeling grateful. “You don’t really appreciate the effect of having a lethal disease until it’s not there anymore,” he says. “The world looks different when you have a future.”
This article was first published on Leaps.org on March 24, 2022.
This Startup Uses Dust to Fight Sweatshops
"Dust thou art, and unto dust shalt thou return." Whoever wrote that famous line probably didn't realize that dust actually contains a secret weapon.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain."
Far from being a collection of mere inanimate particles, dust is now recognized as a powerful tool filled with living sensors. Studying those sensors can reveal an object's location history, which can help brands fight unethical manufacturing.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain," explains Jessica Green, the CEO of Phylagen, a San-Francisco-based company that she co-founded in 2014.
So how does the technology work?
Dust gathers everywhere—on our bodies, on objects—and that dust contains microbes like bacteria and viruses. Just as we humans have our own unique microbiomes, research has shown that physical locations have their own identifiable patterns of microbes as well. Visiting a place means you may pick up its microbial fingerprint in the dust that settles on you. The DNA of those microbes can later be sequenced in a lab and matched back to the place of origin.
"Your environment is constantly imprinted on you and vice versa," says Justin Gallivan, the director of the Biotechnology Office at DARPA, the research and defense arm of the Pentagon, which is funding Phylagen. "If we have a microbial map of the world," he posits, "can we infer an object's transit history?"
So far, Phylagen has shown that it's possible to identify where a ship came from based on the unique microbial populations it picked up at different naval ports. In another experiment, the sampling technology allowed researchers to determine where a person had walked within 1 kilometer in San Francisco, because of the microbes picked up by their shoes.
Data scientist Roxana Hickey, left, and CEO Jessica Green of Phylagen.
One application of this technology is to help companies that make products abroad. Such companies are very interested in determining exactly where their products are coming from, especially if foreign subcontractors are involved.
"In retail and apparel, often the facilities performing the subcontracting are not up to the same code that the brands require their suppliers to be, so there could be poor working conditions," says Roxana Hickey, a data scientist at Phylagen. "A supplier might use a subcontractor to save on the bottom line, but unethical practices are very damaging to the brand."
Before this technology was developed, brands sometimes faced a challenge figuring out what was going on in their supply chain. But now a product can be tested upon arrival in the States; its microbial signature can theoretically be analyzed and matched against a reference database to help determine if its DNA pattern matches that of the place where the product was purported to have been made.
Phylagen declined to elaborate further about how their process works, such as how they are building a database of reference samples, and how consistent a microbial population remains across a given location.
As the technology grows more robust, though, one could imagine numerous other applications, like in police work and forensics. But today, Phylagen is solely focused on helping commercial entities bring greater transparency to their operations so they can root out unauthorized subcontracting.
Then those unethical suppliers can – shall we say – bite the dust.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Surfing for Science: A Fin Sensor Is Making Waves
For David Walden, a Southern Californian, surfing is a lifestyle, not a hobby. The 38-year-old works nights at a seafood restaurant to leave his mornings free for surfing.
While the surfers are doing what they love, they are also collecting information that is helping scientists better understand the ocean.
"Once you fall in love with the ocean, you need it like a daily cleanse or refresher," he says. "The positive mental and physical effects of the ocean, the endorphins and dopamine, keep you addicted in a good way."
Given his dedication to surfing, Walden was delighted when he became one of more than 200 surfers last year to test Smartfin, a 5-1/2-inch surfboard fin that contains a circuit board, a rechargeable battery, a GPS device, a sensor that captures temperature to one-hundredth of a degree, and a motion sensor that tracks the movement of the waves. While Walden and his fellow surfers are doing what they love, they are also collecting information that is helping scientists better understand the health of the near-shore ocean and how its chemistry is shifting due to climate change.
"I'm excited to be a part of it," Walden says. "I like to tell people I surf for science."
Back on shore, the surfers download the Smartfin data via a smartphone app so they can be accessed by scientists and other interested parties. (You can see where Smartfin surfers go at this interactive map.)
By putting sensors directly onto surfboards, oceanographers can collect data to help them better understand the global-warming related changes occurring in coastal oceans in temperature, salinity, and pH, all properties that have huge implications for the species that live in near-shore ecosystems.
There is much unknown about coastal waters because it's so difficult to obtain meaningful measurements. Traditional methods to monitor the close shore, such as bottle samples and buoys, are time consuming and expensive and tend to get damaged by the surf.
The Smartfin is the brainchild of Dr. Andy Stern, a retired neurologist. He and his brother-in-law, sculptor and filmmaker Todd McGrain, run The Lost Bird Project, a nonprofit devoted to raising awareness about climate change and other environmental issues. Stern brought his super fin idea to engineer Benjamin Thompson, who spent several years creating a prototype in his garage workshop. Smartfin was further developed by scientists at the Scripps Institution of Oceanography at the University of California at San Diego.
"The big challenge was to make a sensor small enough to fit in the fin but still produce good measurements," says Andreas Andersson, an associate professor of geoscience research at Scripps.
The Surfrider Foundation, a surfer-led nonprofit environmental organization, came aboard two years ago to distribute the Smartfin to its San Diego members.
Smartfin has also made a splash with scientists at the University of the Sunshine Coast in Queensland on the eastern coast of Australia. They are using the fin's temperature sensor to better understand how climate change is affecting the movement and distribution of marine life. And at the Plymouth Marine Laboratory in Plymouth, United Kingdom, the Smartfin's precise temperature readings of the near-shore ocean's surface are being used to improve the accuracy of satellites that monitor the ocean from hundreds of miles away.
"It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin."
"The hope is that Smartfin will improve the satellite measurements, which could improve the retrieval of temperature data around the world," says Dr. Phil Bresnahan, Smartfin's lead engineer at Scripps. In the future, the fin will include sensors to measure pH, chlorophyll (algae), dissolved oxygen, and turbidity (water clarity).
Stern envisions a time when thousands of surfers, paddle boarders, and other water enthusiasts worldwide will have Smartfins and be downloading data for scientists and environmentalists. Right now, there are approximately 70 surfers in the San Diego area using Smartfin and an additional 30 globally.
Scientists have plenty of evidence that global warming is largely caused by humans. Now they are trying to figure out what the long-term effects of climate change may be. For example, scientists are trying to predict which sections of coral reef, which house 25 percent of marine species, are most vulnerable so interventions can be developed to save them. Because of its small size, Smartfin is ideal to measure temperature changes in coral reefs.
Smartfin was also intended to be an educational tool. "It's a great way to start a different conversation about climate change," says Stern. "It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin. People want to hear more."
Turning surfers into citizen scientists makes perfect sense, says David Pasquini, 35, a longtime surfer who works for the British Consulate General's office in Oceanside, Calif. "Anyone who spends a lot of time in the ocean is aware of the changes happening in the ecosystem, the climate," says Pasquini. "Everyone asks, 'What can I do?'" Surfing with Smartfin, Pasquini feels like he is giving back.
"I know the data will be analyzed and eventually used to make a policy that helps with climate change. That's a great feeling--just by surfing, doing something you love, you're contributing."