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.
Scientists Just Created Liquid Solar Power That Can Be Stored for 18 Years
Look no further than this week's climate strikes for evidence that millions of people are passionate about curbing global warming.
Unlike relatively limited solar panel energy storage, norbornadiene can potentially maintain its potency for years.
But even potential solutions, like alternative meats, have their own challenges. Some scientists are putting their focus on the sun to help balance out our energy consumption.
In fact, they are gathering solar power so pure that, until recently, capturing it was an impossibility.
The Lowdown
A group of Swedish scientists has created a liquid called norbornadiene. This liquid sunshine can capture up to 30 percent of raw solar power. To put it in perspective, the best publicly available solar panels can harness 21 percent. Norbornadiene would bring in about 50 percent more power – a significant difference in energy efficiency.
Most notably, unlike relatively limited solar panel energy storage, norbornadiene can potentially maintain its potency for years. We could have the ability to collect and store premium solar power, making it easier for current and future generations to use fossil and nuclear fuel alternatives.
"The norbornadiene molecules that we have made have very good properties, in terms of solar energy capture efficiency, storage time and energy density," says team lead Dr. Kasper Moth-Poulson of the Chamlers University of Technology. "They can store energy without the need for insulation materials for 18 or more years."
Next Up
Swedish scientist Moth-Poulsen and his team have been testing the norbornadiene on the physics building roof at the Chalmers University of Technology. Once activated, it heats up to just below boiling and provides enough power to be useful.
The energy density is 250 watt-hours per kilogram, twice the strength of Tesla's popular Powerall battery.
It requires potentially toxic solvents, like a cobalt-based activator, to transform into its full potential. The team is currently trying to find less-hazardous catalysts to help transform the norbornadiene to its active form, quadricyclane. Exposing it to sunlight is the main way to reactivate the norbornadiene's power. Over time, scientists will likely make it more efficient with less toxic agents.
The energy density is 250 watt-hours per kilogram, twice the strength of Tesla's popular Powerall battery.
Open Questions
The biggest question is safety, perceived or otherwise: Are you ready to drive around with 250 kWh of pure solar in your Hyundai? Norbornadiene may be stable in a hermetically sealed lab, but sculpting it for everyday use requires another level of security.
The half-life of the sunshine power is also an estimate, too. The challenge with new scientific substances is you don't know how the matter will evolve over time. It is easy to be overly optimistic about this one discovery being the key to our energy needs. For the time being, it is wiser to look at norbornadiene as a progressive step rather than a revolutionary one.
Even at its least effective, norbornadiene and its related material is a step toward us utilizing the one natural resource that won't run out for generations. In the short-term, a stable form of it could offset our fossil and nuclear fuel use and even help lower the carbon footprint made by long-distance transportation. It will be fascinating to see what future aircraft builders, home designers and even car manufacturers do as the solar technology conversation heats up.
Moth-Poulsen wants norbornadiene to be a definitive part of the climate change puzzle.
"I hope that in five years, we will see the first products based on our molecules and could help mitigate the daily variations in temperature," he says. "This will lead to increased thermal comfort and reduced energy consumption for heating and cooling."
Virtual Reality is Making Medical Care for Kids Less Scary and Painful
A blood draw is not normally a fun experience, but these days, virtual reality technology is changing that.
Instead of watching a needle go into his arm, a child wearing a VR headset at Children's Hospital Los Angeles can play a game throwing balls at cartoon bears. In Seattle, at the University of Washington, a burn patient can immerse herself in a soothing snow scene. And at the University of Miami Hospital, a five-minute skin biopsy can become an exciting ride at an amusement park.
VR is transforming once-frightening medical encounters for kids, from blood draws to biopsies to pre-surgical prep, into tolerable ones.
It's literally a game changer, says pediatric neurosurgeon Kurtis Auguste, who uses the tool to help explain pending operations to his young patients and their families. The virtual reality 3-D portrait of their brain is recreated from an MRI, originally to help plan the surgery. The image of normally bland tissue is painted with false colors to better see the boundaries and anomalies of each component. It can be rotated, viewed from every possible angle, zoomed in and out; incisions can be made and likely results anticipated. Auguste has extended its use to patients and families.
"The moment you put these headsets on the kids, we immediately have a link, because honestly, this is how they communicate with each other," says Auguste. "We're all sitting around the table playing games. It's really bridged the distance between me, the pediatric specialist, and my patients" at the Benioff Children's Hospital Oakland, now affiliated with the University of California San Francisco School of Medicine.
The VR experience engages people where they are, immersing them in the environment rather than lecturing them. And it seems to work in all environments, across age and cultural differences, leading to a better grasp of what will be undertaken. That understanding is crucial to meaningful informed consent for surgery. It is particularly relevant for safety-net hospitals, which includes most children's hospitals, because often members of the families were born elsewhere and may have limited understanding of English, not to mention advanced medicine.
Targeting pain
"We're trying to target ways that we can decrease pain, anxiety, fear – what people usually experience as a function of a needle," says Jeffrey Gold, a pioneer in adapting VR at Children's Hospital Los Angeles. He ran the pain clinic there and in 2004 initially focused on phlebotomy, simple blood draws. Many of their kids require frequent blood draws to monitor serious chronic conditions such as diabetes, HIV infection, sickle cell disease, and other conditions that affect the heart, liver, kidneys and other organs.
The scientific explanation of how VR works for pain relief draws upon two basic principles of brain function. The first is "top down inhibition," Gold explains. "We all have the inherent capacity to turn down signals once we determine that signal is no longer harmful, dangerous, hurtful, etc. That's how our brain operates on purpose. It's not just a distraction, it's actually your brain stopping the pain signal at the spinal cord before it can fire all the way up to the frontal lobe."
Second is the analgesic effect from endorphins. "If you're in a gaming environment, and you're having fun and you're laughing and giggling, you are actually releasing endorphins...a neurochemical reaction at the synaptic level of the brain," he says.
Part of what makes VR effective is "what's called a cognitive load, where you have to actually learn something and do something," says Gold. He has worked with developers on a game call Bear Blast, which has proven to be effective in a clinical trial for mitigating pain. But he emphasizes, it is not a one-size-fits all; the programs and patients need to be evaluated to understand what works best for each case.
Gold was a bit surprised to find that VR "actually facilitates quicker blood draws," because the staff doesn't have to manage the kids' anxiety, so "they require fewer needle sticks." The kids, parents, and staff were all having a good time, "and that's a big win when everybody is benefiting." About two years ago the hospital made VR an option that patients can request in the phlebotomy lab, and about half of kids age 4 and older choose to do so.
The technology "gets the kids engaged and performing the activity the way we want them to" to maximize recovery.
VR reduces or eliminates the need to use sedation or anesthesia, which carries a small but real risk of an adverse reaction. And important to parents, it eliminates the recovery time from using sedation, which shortens the visit and time missed from school and work.
A more intriguing question is whether reducing fear and anxiety in early-life experiences with the healthcare system through activities like VR will have a long-term affect on kids' attitudes toward medicine as they grow older. "If you're a screaming meemie when you come get your blood draw when you're five or seven, you're still that anxious adolescent or adult who is all quivering and sweating and avoiding healthcare," Gold says. "That's a longitudinal health outcome I'd love to get my hands on in 10-15 years from now."
Broader applications
Dermatologist Hadar Lev-Tov read about the use of VR to treat pain and decided to try it in his practice at the University of Miami Hospital. He thought, "OK, this is low risk, it's easy to do. So we got some equipment and got it done." It was so affordable he paid for it out of his own pocket, rather than wait to go through administrative channels. The results were so interesting that he decided to publish it as a series of case studies with a wide variety of patients and types of procedures.
Some of them, such as freezing off warts, are not particularly painful. "But there can be a lot of anxiety, especially for kids, which can be worse than pain and can disrupt the procedure." It can trigger a non-rational, primal fight or flight response in the limbic region of the brain.
Adults understand the need for a biopsy of a skin growth and tolerate what might be a momentary flick of pain. "But for a kid you think twice about a biopsy, both because it's a hassle and because it could be a traumatic event for a child," says Lev-Tov. VR has helped to allay such fears and improve medical care.
Integrating VR into practice has been relatively easy, primarily focusing on simple training for staff and ensuring that standard infection control practices are used in handling equipment that is used by different patients. More mundane issues are ensuring that the play back and wi-fi equipment are functioning properly. He has had a few complaints from kids when the procedure is competed and the VR is turned off prematurely, which is why he favors programs like a roller coaster ride that lasts about five minutes, ample time to take a biopsy or two.
The future is today
The pediatric neurosurgeon Auguste is collaborating with colleagues at Oakland Children's to expand use of VR into different areas of care. Cancer specialists often use a port, a bubble installed under the skin in the chest of the child, to administer chemotherapy. But the young patient's curiosity often draws their attention downward to the port and their chin can potentially contaminate or obstruct it, interfering with the procedure. So the team developed a VR game involving birds that requires players to move their heads upward, away from the port, improving administration of the drugs and reducing the risk of infection.
Innovative use of VR just may be one tool that actually makes kids eager to visit the doctor.
Other games are being developed for rehabilitation that require the use of specific nerve and muscle combinations. The technology "gets the kids engaged and performing the activity the way we want them to" to maximize recovery, Auguste explains. "We can monitor their progress by the score on the game, and if it plateaus, maybe switch to another game."
Another project is trying to ease the anxiety and confusion of the patient and family experience within the hospital itself. Hospital staff are creating a personalized VR introductory walking tour that leads from the parking garage through the maze of structures and corridors in the hospital complex to Dr. Auguste's office, phlebotomy, the MRI site, and other locations they might visit. The goal is to make them familiar with key landmarks before they even set foot in the facility. "So when they come the day of the visit they have already taken that exact same path, hopefully more than once."
"They don't miss their MRI appointment and therefore they don't miss their clinical appointment with me," says Auguste. It reduces patient anxiety about the encounter and from the hospital's perspective, it will reduce costs of missed and rescheduled visits simply because patients did not go to the right place at the right time.
The VR visit will be emailed to patients ahead of time and they can watch it on a smartphone installed in a disposable cardboard viewer. Oakland Children's hopes to have the system in place by early next year. Auguste says their goal in using VR, like other health care providers across the country, is "to streamline the entire patient experience."
Innovative use of VR just may be one tool that actually makes kids eager to visit the doctor. That would be a boon to kids, parents, and the health of America.