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.
By mid-March, Alpha Lee was growing restless. A pioneer of AI-driven drug discovery, Lee leads a team of researchers at the University of Cambridge, but his lab had been closed amidst the government-initiated lockdowns spreading inexorably across Europe.
If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Having spoken to his collaborators across the globe – many of whom were seeing their own experiments and research projects postponed indefinitely due to the pandemic – he noticed a similar sense of frustration and helplessness in the face of COVID-19.
While there was talk of finding a novel treatment for the virus, Lee was well aware the process was likely to be long and laborious. Traditional methods of drug discovery risked suffering the same fate as the efforts to find a cure for SARS in the early 2000, which took years and were ultimately abandoned long before a drug ever reached the market.
To avoid such an outcome, Lee was convinced that global collaboration was required. Together with a collection of scientists in the UK, US and Israel, he launched the 'COVID Moonshot' – a project which encouraged chemists worldwide to share their ideas for potential drug designs. If the Moonshot proves successful, they hope it could serve as a future benchmark for finding new medicines for chronic diseases.
Solving a Complex Jigsaw
In February, ShanghaiTech University published the first detailed snapshots of the SARS-CoV-2 coronavirus's proteins using a technique called X-ray crystallography. In particular, they revealed a high-resolution profile of the virus's main protease – the part of its structure that enables it to replicate inside a host – and the main drug target. The images were tantalizing.
"We could see all the tiny pieces sitting in the structure like pieces of a jigsaw," said Lee. "All we needed was for someone to come up with the best idea of joining these pieces together with a drug. Then you'd be left with a strong molecule which sits in the protease, and stops it from working, killing the virus in the process."
Normally, ideas for how best to design such a drug would be kept as carefully guarded secrets within individual labs and companies due to their potential value. But as a result, the steady process of trial and error to reach an optimum design can take years to come to fruition.
However, given the scale of the global emergency, Lee felt that the scientific community would be open to collective brainstorming on a mass scale. "Big Pharma usually wouldn't necessarily do this, but time is of the essence here," he said. "It was a case of, 'Let's just rethink every drug discovery stage to see -- ok, how can we go as fast as we can?'"
On March 13, he launched the COVID moonshot, calling for chemists around the globe to come up with the most creative ideas they could think of, on their laptops at home. No design was too weird or wacky to be considered, and crucially nothing would be patented. The entire project would be done on a not-for-profit basis, meaning that any drug that makes it to market will have been created simply for the good of humanity.
It caught fire: Within just two weeks, more than 2,300 potential drug designs had been submitted. By the middle of July, over 10,000 had been received from scientists around the globe.
The Road Toward Clinical Trials
With so many designs to choose from, the team has been attempting to whittle them down to a shortlist of the most promising. Computational drug discovery experts at Diamond and the Weizmann Institute of Science in Rehovot, Israel, have enabled the Moonshot team to develop algorithms for predicting how quick and easy each design would be to make, and to predict how well each proposed drug might bind to the virus in real life.
The latter is an approach known as computational covalent docking and has previously been used in cancer research. "This was becoming more popular even before COVID-19, with several covalent drugs approved by the FDA in recent years," said Nir London, professor of organic chemistry at the Weizmann Institute, and one of the Moonshot team members. "However, all of these were for oncology. A covalent drug against SARS-CoV-2 will certainly highlight covalent drug-discovery as a viable option."
Through this approach, the team have selected 850 compounds to date, which they have manufactured and tested in various preclinical trials already. Fifty of these compounds - which appear to be especially promising when it comes to killing the virus in a test tube – are now being optimized further.
Lee is hoping that at least one of these potential drugs will be shown to be effective in curing animals of COVID-19 within the next six months, a step that would allow the Moonshot team to reach out to potential pharmaceutical partners to test their compounds in humans.
Future Implications
If the project does succeed, some believe it could open the door to scientific crowdsourcing as a future means of generating novel medicine ideas for other diseases. Frank von Delft, professor of protein science and structural biology at the University of Oxford's Nuffield Department of Medicine, described it as a new form of 'citizen science.'
"There's a vast resource of expertise and imagination that is simply dying to be tapped into," he said.
Others are slightly more skeptical, pointing out that the uniqueness of the current crisis has meant that many scientists were willing to contribute ideas without expecting any future compensation in return. This meant that it was easy to circumvent the traditional hurdles that prevent large-scale global collaborations from happening – namely how to decide who will profit from the final product and who will hold the intellectual property (IP) rights.
"I think it is too early to judge if this is a viable model for future drug discovery," says London. "I am not sure that without the existential threat we would have seen so many contributions, and so many people and institutions willing to waive compensation and future royalties. Many scientists found themselves at home, frustrated that they don't have a way to contribute to the fight against COVID-19, and this project gave them an opportunity. Plus many can get behind the fact that this project has no associated IP and no one will get rich off of this effort. This breaks down a lot of the typical barriers and red-tape for wider collaboration."
"If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
However the Moonshot team believes that if they can succeed, it will at the very least send a strong statement to policy makers and the scientific community that greater efforts should be made to make such large-scale collaborations more feasible.
"All across the scientific world, we've seen unprecedented adoption of open-science, collaboration and collegiality during this crisis, perhaps recognizing that only a coordinated global effort could address this global challenge," says London. "If a drug would sprout from one of these crowdsourced ideas, it would serve as a very powerful argument to consider this mode of drug discovery further in the future."
[An earlier version of this article was published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]
World’s First “Augmented Reality” Contact Lens Aims to Revolutionize Much More Than Medicine
Imagine a world without screens. Instead of endlessly staring at your computer or craning your neck down to scroll through social media feeds and emails, information simply appears in front of your eyes when you need it and disappears when you don't.
"The vision is super clear...I was reading the poem with my eyes closed."
No more rude interruptions during dinner, no more bumping into people on the street while trying to follow GPS directions — just the information you want, when you need it, projected directly onto your visual field.
While this screenless future sounds like science fiction, it may soon be a reality thanks to the new Silicon Valley startup Mojo Vision, creator of the world's first smart contact lens. With a 14,000 pixel-per-inch display with eye-tracking, image stabilization, and a custom wireless radio, the Mojo smart lens bills itself the "smallest and densest dynamic display ever made." Unlike current augmented reality wearables such as Google Glass or ThirdEye, which project images onto a glass screen, the Mojo smart lens can project images directly onto the retina.
A current prototype displayed at the Consumer Electronics Show earlier this year in Las Vegas includes a tiny screen positioned right above the most sensitive area of the pupil. "[The Mojo lens] is a contact lens that essentially has wireless power and data transmission for a small micro LED projector that is placed over the center of the eye," explains David Hobbs, Director of Product Management at Mojo Vision. "[It] displays critical heads-up information when you need it and fades into the background when you're ready to continue on with your day."
Eventually, Mojo Visions' technology could replace our beloved smart devices but the first generation of the Mojo smart lens will be used to help the 2.2 billion people globally who suffer from vision impairment.
"If you think of the eye as a camera [for the visually impaired], the sensors are not working properly," explains Dr. Ashley Tuan, Vice President of Medical Devices at Mojo Vision and fellow of the American Academy of Optometry. "For this population, our lens can process the image so the contrast can be enhanced, we can make the image larger, magnify it so that low-vision people can see it or we can make it smaller so they can check their environment." In January of this year, the FDA granted Breakthrough Device Designation to Mojo, allowing them to have early and frequent discussions with the FDA about technical, safety and efficacy topics before clinical trials can be done and certification granted.
For now, Dr. Tuan is one of the few people who has actually worn the Mojo lens. "I put the contact lens on my eye. It was very comfortable like any contact lenses I've worn before," she describes. "The vision is super clear and then when I put on the accessories, suddenly I see Yoda in front of me and I see my vital signs. And then I have my colleague that prepared a beautiful poem that I loved when I was young [and] I was reading the poem with my eyes closed."
At the moment, there are several electronic glasses on the market like Acesight and Nueyes Pro that provide similar solutions for those suffering from visual impairment, but they are large, cumbersome, and highly visible. Mojo lens would be a discreet, more comfortable alternative that offers users more freedom of movement and independence.
"In the case of augmented-reality contact lenses, there could be an opportunity to improve the lives of people with low vision," says Dr. Thomas Steinemann, spokesperson for the American Academy of Ophthalmology and professor of ophthalmology at MetroHealth Medical Center in Cleveland. "There are existing tools for people currently living with low vision—such as digital apps, magnifiers, etc.— but something wearable could provide more flexibility and significantly more aid in day-to-day tasks."
As one of the first examples of "invisible computing," the potential applications of Mojo lens in the medical field are endless.
According to Dr. Tuan, the visually impaired often suffer from depression due to their lack of mobility and 70 percent of them are underemployed. "We hope that they can use this device to gain their mobility so they can get that social aspect back in their lives and then, eventually, employment," she explains. "That is our first and most important goal."
But helping those with low visual capabilities is only Mojo lens' first possible medical application; augmented reality is already being used in medicine and is poised to revolutionize the field in the coming decades. For example, Accuvein, a device that uses lasers to provide real-time images of veins, is widely used by nurses and doctors to help with the insertion of needles for IVs and blood tests.
According to the National Center for Biotechnology Information, augmentation of reality has been used in surgery for many years with surgeons using devices such as Google Glass to overlay critical information about their patients into their visual field. Using software like the Holographic Navigation Platform by Scopsis, surgeons can see a mixed-reality overlay that can "show you complicated tumor boundaries, assist with implant placements and guide you along anatomical pathways," its developers say.
However, according to Dr. Tuan, augmented reality headsets have drawbacks in the surgical setting. "The advantage of [Mojo lens] is you don't need to worry about sweating or that the headset or glasses will slide down to your nose," she explains "Also, our lens is designed so that it will understand your intent, so when you don't want the image overlay it will disappear, it will not block your visual field, and when you need it, it will come back at the right time."
As one of the first examples of "invisible computing," the potential applications of Mojo lens in the medical field are endless. Possibilities include live translation of sign language for deaf people; helping those with autism to read emotions; and improving doctors' bedside manner by allowing them to fully engage with patients without relying on a computer.
"[By] monitoring those blood vessels we can [track] chronic disease progression: high blood pressure, diabetes, and Alzheimer's."
Furthermore, the lens could be used to monitor health issues. "We have image sensors in the lens right now that point to the world but we can have a camera pointing inside of your eye to your retina," says Dr. Tuan, "[By] monitoring those blood vessels we can [track] chronic disease progression: high blood pressure, diabetes, and Alzheimer's."
For the moment, the future medical applications of the Mojo lens are still theoretical, but the team is confident they can eventually become a reality after going through the proper regulatory review. The company is still in the process of design, prototype and testing of the lens, so they don't know exactly when it will be available for use, but they anticipate shipping the first available products in the next couple of years. Once it does go to market, it will be available by prescription only for those with visual impairments, but the team's goal is to bring it to broader consumer markets pending regulatory clearance.
"We see that right now there's a unique opportunity here for Mojo lens and invisible computing to help to shape what the next decade of technology development looks like," explains David Hobbs. "We can use [the Mojo lens] to better serve us as opposed to us serving technology better."