A recent study by researchers at the University of Pennsylvania examined how CAR-T therapy helped Doug Olson beat a cancer death sentence for over a decade - and how it could work for more people.
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.
Rodney Gorham, an Australian living with ALS, has reconnected with the world, thanks to a brain-machine interface called the Stentrode.
The brain-computer interface enabling this feat is called the Stentrode. It's the brainchild of Synchron, a company backed by Amazon’s Jeff Bezos and Microsoft cofounder Bill Gates. After Gorham’s neurologist recommended that he try it, he became one of the first volunteers to have an 8mm stent, laced with small electrodes, implanted into his jugular vein and guided by a surgeon into a blood vessel near the part of his brain that controls movement.
After arriving at their destination, these tiny sensors can detect neural activity. They relay these messages through a small receiver implanted under the skin to a computer, which then translates the information into words. This minimally invasive surgery takes a day and is painless, according to Gorham. Recovery time is typically short, about two days.
When a paralyzed patient thinks about trying to move their arms or legs, the motor cortex will fire patterns that are specific to the patient’s thoughts.
When a paralyzed patient such as Gorham thinks about trying to move their arms or legs, the motor cortex will fire patterns that are specific to the patient’s thoughts. This pattern is detected by the Stentrode and relayed to a computer that learns to associate this pattern with the patient’s physical movements. The computer recognizes thoughts about kicking, making a fist and other movements as signals for clicking a mouse or pushing certain letters on a keyboard. An additional eye-tracking device controls the movement of the computer cursor.
The process works on a letter by letter basis. That’s why longer and more nuanced responses often involve some trial and error. “I have been using this for about two years, and I enjoy the sessions,” Gorham typed during our chat session. Zafar Faraz, field clinical engineer at Synchron, sat next to Gorham, providing help when required. Gorham had suffered without internet access, but now he looks forward to surfing the web and playing video games.
Gorham, age 63, has been enjoying Stentrode sessions for about two years.
Rodeny Dekker
The BCI revolution
In the summer of 2021, Synchron became the first company to receive the FDA’s Investigational Device Exemption, which allows research trials on the Stentrode in human patients. This past summer, the company, together with scientists from Icahn School of Medicine at Mount Sinai and the Neurology and Neurosurgery Department at Utrecht University, published a paper offering a framework for how to develop BCIs for patients with severe paralysis – those who can't use their upper limbs to type or use digital devices.
Three months ago, Synchron announced the enrollment of six patients in a study called COMMAND based in the U.S. The company will seek approval next year from the FDA to make the Stentrode available for sale commercially. Meanwhile, other companies are making progress in the field of BCIs. In August, Neuralink announced a $280 million financing round, the biggest fundraiser yet in the field. Last December, Synchron announced a $75 million financing round. “One thing I can promise you, in five years from now, we’re not going to be where we are today. We're going to be in a very different place,” says Elad I. Levy, professor of neurosurgery and radiology at State University of New York in Buffalo.
The risk of hacking exists, always. Cybercriminals, for example, might steal sensitive personal data for financial reasons, blackmailing, or to spread malware to other connected devices while extremist groups could potentially hack BCIs to manipulate individuals into supporting their causes or carrying out actions on their behalf.
“The prospect of bestowing individuals with paralysis a renewed avenue for communication and motor functionality is a step forward in neurotech,” says Hayley Nelson, a neuroscientist and founder of The Academy of Cognitive and Behavioral Neuroscience. “It is an exciting breakthrough in a world of devastating, scary diseases,” says Neil McArthur, a professor of philosophy and director of the Centre for Professional and Applied Ethics at the University of Manitoba. “To connect with the world when you are trapped inside your body is incredible.”
While the benefits for the paraplegic community are promising, the Stentrode’s long-term effectiveness and overall impact needs more research on safety. “Potential risks like inflammation, damage to neural tissue, or unexpected shifts in synaptic transmission due to the implant warrant thorough exploration,” Nelson says.
There are also concens about data privacy concerns and the policies of companies to safeguard information processed through BCIs. “Often, Big Tech is ahead of the regulators because the latter didn’t envisage such a turn of events...and companies take advantage of the lack of legal framework to push forward,” McArthur says. Hacking is another risk. Cybercriminals could steal sensitive personal data for financial reasons, blackmailing, or to spread malware to other connected devices. Extremist groups could potentially hack BCIs to manipulate individuals into supporting their causes or carrying out actions on their behalf.
“We have to protect patient identity, patient safety and patient integrity,” Levy says. “In the same way that we protect our phones or computers from hackers, we have to stay ahead with anti-hacking software.” Even so, Levy thinks the anticipated benefits for the quadriplegic community outweigh the potential risks. “We are on the precipice of an amazing technology. In the future, we would be able to connect patients to peripheral devices that enhance their quality of life.”
In the near future, the Stentrode could enable patients to use the Stentrode to activate their wheelchairs, iPods or voice modulators. Synchron's focus is on using its BCI to help patients with significant mobility restrictions—not to enhance the lives of healthy people without any illnesses. Levy says we are not prepared for the implications of endowing people with superpowers.
I wondered what Gorham thought about that. “Pardon my question, but do you feel like you have sort of transcended human nature, being the first in a big line of cybernetic people doing marvelous things with their mind only?” was my last question to Gorham.
A slight smile formed on his lips. In less than a minute, he typed: “I do a little.”
XPRIZE founder and chairman Peter Diamandis launches XPRIZE Healthspan at an event on November 29.
In this competition, called XPRIZE Healthspan, multiple awards are available, depending on what’s achieved, with support from the nonprofit Hevolution Foundation and Chip Wilson, the founder of Lululemon and nonprofit SOLVE FSHD. The biggest prize, $81 million, is for improvements in cognition, muscle and immunity by 20 years. An improvement of 15 years will net $71 million, and 10 years will net $61 million.
In our conversation for this episode, Peter talks about his plans for XPRIZE Healthspan and why exponential technologies make the current era - even with all of its challenges - the most exciting time in human history. We discuss the best mental outlook that supports a person in becoming truly innovative, as well as the downsides of too much risk aversion. We talk about how to overcome the negativity bias in ourselves and in mainstream media, how Peter has shifted his own mindset to become more positive over the years, how to inspire a culture of innovation, Peter’s personal recommendations for lifestyle strategies to live longer and healthier, the innovations we can expect in various fields by 2030, the future of education and the importance of democratizing tech and innovation.
In addition to Peter’s pioneering leadership of XPRIZE, he is also the Executive Founder of Singularity University. In 2014, he was named by Fortune as one of the “World’s 50 Greatest Leaders.” As an entrepreneur, he’s started over 25 companies in the areas of health-tech, space, venture capital and education. He’s Co-founder and Vice-Chairman of two public companies, Celularity and Vaxxinity, plus being Co-founder & Chairman of Fountain Life, a fully-integrated platform delivering predictive, preventative, personalized and data-driven health. He also serves as Co-founder of BOLD Capital Partners, a venture fund with a half-billion dollars under management being invested in exponential technologies and longevity companies. Peter is a New York Times Bestselling author of four books, noted during our conversation and in the show notes of this episode. He has degrees in molecular genetics and aerospace engineering from MIT and holds an M.D. from Harvard Medical School.
Show links
- Peter Diamandis bio
- New XPRIZE Healthspan
- Peter Diamandis books
- 27 XPRIZE competitions and counting
- Life Force by Peter Diamandis and Tony Robbins
- Peter Diamandis Twitter
- Longevity Insider newsletter – AI identifies the news
- Peter Diamandis Longevity Handbook
- Hevolution funding for longevity
XPRIZE Founder Peter Diamandis speaks with Mehmoud Khan, CEO of Hevolution Foundation, at the launch of XPRIZE Healthspan.
Hevolution Foundation