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.
“Virtual Biopsies” May Soon Make Some Invasive Tests Unnecessary
At his son's college graduation in 2017, Dan Chessin felt "terribly uncomfortable" sitting in the stadium. The bouts of pain persisted, and after months of monitoring, a urologist took biopsies of suspicious areas in his prostate.
This innovation may enhance diagnostic precision and promptness, but it also brings ethical concerns to the forefront.
"In my case, the biopsies came out cancerous," says Chessin, 60, who underwent robotic surgery for intermediate-grade prostate cancer at University Hospitals Cleveland Medical Center.
Although he needed a biopsy, as most patients today do, advances in radiologic technology may make such invasive measures unnecessary in the future. Researchers are developing better imaging techniques and algorithms—a form of computer science called artificial intelligence, in which machines learn and execute tasks that typically require human brain power.
This innovation may enhance diagnostic precision and promptness. But it also brings ethical concerns to the forefront of the conversation, highlighting the potential for invasion of privacy, unequal patient access, and less physician involvement in patient care.
A National Academy of Medicine Special Publication, released in December, emphasizes that setting industry-wide standards for use in patient care is essential to AI's responsible and transparent implementation as the industry grapples with voluminous quantities of data. The technology should be viewed as a tool to supplement decision-making by highly trained professionals, not to replace it.
MRI--a test that uses powerful magnets, radio waves, and a computer to take detailed images inside the body--has become highly accurate in detecting aggressive prostate cancer, but its reliability is more limited in identifying low and intermediate grades of malignancy. That's why Chessin opted to have his prostate removed rather than take the chance of missing anything more suspicious that could develop.
His urologist, Lee Ponsky, says AI's most significant impact is yet to come. He hopes University Hospitals Cleveland Medical Center's collaboration with research scientists at its academic affiliate, Case Western Reserve University, will lead to the invention of a virtual biopsy.
A National Cancer Institute five-year grant is funding the project, launched in 2017, to develop a combined MRI and computerized tool to support more accurate detection and grading of prostate cancer. Such a tool would be "the closest to a crystal ball that we can get," says Ponsky, professor and chairman of the Urology Institute.
In situations where AI has guided diagnostics, radiologists' interpretations of breast, lung, and prostate lesions have improved as much as 25 percent, says Anant Madabhushi, a biomedical engineer and director of the Center for Computational Imaging and Personalized Diagnostics at Case Western Reserve, who is collaborating with Ponsky. "AI is very nascent," Madabhushi says, estimating that fewer than 10 percent of niche academic medical centers have used it. "We are still optimizing and validating the AI and virtual biopsy technology."
In October, several North American and European professional organizations of radiologists, imaging informaticists, and medical physicists released a joint statement on the ethics of AI. "Ultimate responsibility and accountability for AI remains with its human designers and operators for the foreseeable future," reads the statement, published in the Journal of the American College of Radiology. "The radiology community should start now to develop codes of ethics and practice for AI that promote any use that helps patients and the common good and should block use of radiology data and algorithms for financial gain without those two attributes."
Overreliance on new technology also poses concern when humans "outsource the process to a machine."
The statement's leader author, radiologist J. Raymond Geis, says "there's no question" that machines equipped with artificial intelligence "can extract more information than two human eyes" by spotting very subtle patterns in pixels. Yet, such nuances are "only part of the bigger picture of taking care of a patient," says Geis, a senior scientist with the American College of Radiology's Data Science Institute. "We have to be able to combine that with knowledge of what those pixels mean."
Setting ethical standards is high on all physicians' radar because the intricacies of each patient's medical record are factored into the computer's algorithm, which, in turn, may be used to help interpret other patients' scans, says radiologist Frank Rybicki, vice chair of operations and quality at the University of Cincinnati's department of radiology. Although obtaining patients' informed consent in writing is currently necessary, ethical dilemmas arise if and when patients have a change of heart about the use of their private health information. It is likely that removing individual data may be possible for some algorithms but not others, Rybicki says.
The information is de-identified to protect patient privacy. Using it to advance research is akin to analyzing human tissue removed in surgical procedures with the goal of discovering new medicines to fight disease, says Maryellen Giger, a University of Chicago medical physicist who studies computer-aided diagnosis in cancers of the breast, lung, and prostate, as well as bone diseases. Physicians who become adept at using AI to augment their interpretation of imaging will be ahead of the curve, she says.
As with other new discoveries, patient access and equality come into play. While AI appears to "have potential to improve over human performance in certain contexts," an algorithm's design may result in greater accuracy for certain groups of patients, says Lucia M. Rafanelli, a political theorist at The George Washington University. This "could have a disproportionately bad impact on one segment of the population."
Overreliance on new technology also poses concern when humans "outsource the process to a machine." Over time, they may cease developing and refining the skills they used before the invention became available, said Chloe Bakalar, a visiting research collaborator at Princeton University's Center for Information Technology Policy.
"AI is a paradigm shift with magic power and great potential."
Striking the right balance in the rollout of the technology is key. Rushing to integrate AI in clinical practice may cause harm, whereas holding back too long could undermine its ability to be helpful. Proper governance becomes paramount. "AI is a paradigm shift with magic power and great potential," says Ge Wang, a biomedical imaging professor at Rensselaer Polytechnic Institute in Troy, New York. "It is only ethical to develop it proactively, validate it rigorously, regulate it systematically, and optimize it as time goes by in a healthy ecosystem."
How Emerging Technologies Can Help Us Fight the New Coronavirus
In nature, few species remain dominant for long. Any sizable population of similar individuals offers immense resources to whichever parasite can evade its defenses, spreading rapidly from one member to the next.
Which will prove greater: our defenses or our vulnerabilities?
Humans are one such dominant species. That wasn't always the case: our hunter-gatherer ancestors lived in groups too small and poorly connected to spread pathogens like wildfire. Our collective vulnerability to pandemics began with the dawn of cities and trade networks thousands of years ago. Roman cities were always demographic sinks, but never more so than when a pandemic agent swept through. The plague of Cyprian, the Antonine plague, the plague of Justinian – each is thought to have killed over ten million people, an appallingly high fraction of the total population of the empire.
With the advent of sanitation, hygiene, and quarantines, we developed our first non-immunological defenses to curtail the spread of plagues. With antibiotics, we began to turn the weapons of microbes against our microbial foes. Most potent of all, we use vaccines to train our immune systems to fight pathogens before we are even exposed. Edward Jenner's original vaccine alone is estimated to have saved half a billion lives.
It's been over a century since we suffered from a swift and deadly pandemic. Even the last deadly influenza of 1918 killed only a few percent of humanity – nothing so bad as any of the Roman plagues, let alone the Black Death of medieval times.
How much of our recent winning streak has been due to luck?
Much rides on that question, because the same factors that first made our ancestors vulnerable are now ubiquitous. Our cities are far larger than those of ancient times. They're inhabited by an ever-growing fraction of humanity, and are increasingly closely connected: we now routinely travel around the world in the course of a day. Despite urbanization, global population growth has increased contact with wild animals, creating more opportunities for zoonotic pathogens to jump species. Which will prove greater: our defenses or our vulnerabilities?
The tragic emergence of coronavirus 2019-nCoV in Wuhan may provide a test case. How devastating this virus will become is highly uncertain at the time of writing, but its rapid spread to many countries is deeply worrisome. That it seems to kill only the already infirm and spare the healthy is small comfort, and may counterintuitively assist its spread: it's easy to implement a quarantine when everyone infected becomes extremely ill, but if carriers may not exhibit symptoms as has been reported, it becomes exceedingly difficult to limit transmission. The virus, a distant relative of the more lethal SARS virus that killed 800 people in 2002 to 2003, has evolved to be transmitted between humans and spread to 18 countries in just six weeks.
Humanity's response has been faster than ever, if not fast enough. To its immense credit, China swiftly shared information, organized and built new treatment centers, closed schools, and established quarantines. The Coalition for Epidemic Preparedness Innovations, which was founded in 2017, quickly funded three different companies to develop three different varieties of vaccine: a standard protein vaccine, a DNA vaccine, and an RNA vaccine, with more planned. One of the agreements was signed after just four days of discussion, far faster than has ever been done before.
The new vaccine candidates will likely be ready for clinical trials by early summer, but even if successful, it will be additional months before the vaccine will be widely available. The delay may well be shorter than ever before thanks to advances in manufacturing and logistics, but a delay it will be.
The 1918 influenza virus killed more than half of its victims in the United Kingdom over just three months.
If we faced a truly nasty virus, something that spreads like pandemic influenza – let alone measles – yet with the higher fatality rate of, say, H7N9 avian influenza, the situation would be grim. We are profoundly unprepared, on many different levels.
So what would it take to provide us with a robust defense against pandemics?
Minimize the attack surface: 2019-nCoV jumped from an animal, most probably a bat, to humans. China has now banned the wildlife trade in response to the epidemic. Keeping it banned would be prudent, but won't be possible in all nations. Still, there are other methods of protection. Influenza viruses commonly jump from birds to pigs to humans; the new coronavirus may have similarly passed through a livestock animal. Thanks to CRISPR, we can now edit the genomes of most livestock. If we made them immune to known viruses, and introduced those engineered traits to domesticated animals everywhere, we would create a firewall in those intermediate hosts. We might even consider heritably immunizing the wild organisms most likely to serve as reservoirs of disease.
None of these defenses will be cheap, but they'll be worth every penny.
Rapid diagnostics: We need a reliable method of detection costing just pennies to be available worldwide inside of a week of discovering a new virus. This may eventually be possible thanks to a technology called SHERLOCK, which is based on a CRISPR system more commonly used for precision genome editing. Instead of using CRISPR to find and edit a particular genome sequence in a cell, SHERLOCK programs it to search for a desired target and initiate an easily detected chain reaction upon discovery. The technology is capable of fantastic sensitivity: with an attomolar (10-18) detection limit, it senses single molecules of a unique DNA or RNA fingerprint, and the components can be freeze-dried onto paper strips.
Better preparations: China acted swiftly to curtail the spread of the Wuhan virus with traditional public health measures, but not everything went as smoothly as it might have. Most cities and nations have never conducted a pandemic preparedness drill. Best give people a chance to practice keeping the city barely functional while minimizing potential exposure events before facing the real thing.
Faster vaccines: Three months to clinical trials is too long. We need a robust vaccine discovery and production system that can generate six candidates within a week of the pathogen's identification, manufacture a million doses the week after, and scale up to a hundred million inside of a month. That may be possible for novel DNA and RNA-based vaccines, and indeed anything that can be delivered using a standardized gene therapy vector. For example, instead of teaching each person's immune system to evolve protective antibodies by showing it pieces of the virus, we can program cells to directly produce known antibodies via gene therapy. Those antibodies could be discovered by sifting existing diverse libraries of hundreds of millions of candidates, computationally designed from scratch, evolved using synthetic laboratory ecosystems, or even harvested from the first patients to report symptoms. Such a vaccine might be discovered and produced fast enough at scale to halt almost any natural pandemic.
Robust production and delivery: Our defenses must not be vulnerable to the social and economic disruptions caused by a pandemic. Unfortunately, our economy selects for speed and efficiency at the expense of robustness. Just-in-time supply chains that wing their way around the world require every node to be intact. If workers aren't on the job producing a critical component, the whole chain breaks until a substitute can be found. A truly nasty pandemic would disrupt economies all over the world, so we will need to pay extra to preserve the capacity for independent vertically integrated production chains in multiple nations. Similarly, vaccines are only useful if people receive them, so delivery systems should be as robustly automated as possible.
None of these defenses will be cheap, but they'll be worth every penny. Our nations collectively spend trillions on defense against one another, but only billions to protect humanity from pandemic viruses known to have killed more people than any human weapon. That's foolish – especially since natural animal diseases that jump the species barrier aren't the only pandemic threats.
We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural.
The complete genomes of all historical pandemic viruses ever to have been sequenced are freely available to anyone with an internet connection. True, these are all agents we've faced before, so we have a pre-existing armory of pharmaceuticals and vaccines and experience. There's no guarantee that they would become pandemics again; for example, a large fraction of humanity is almost certainly immune to the 1918 influenza virus due to exposure to the related 2009 pandemic, making it highly unlikely that the virus would take off if released.
Still, making the blueprints publicly available means that a large and growing number of people with the relevant technical skills can single-handedly make deadly biological agents that might be able to spread autonomously -- at least if they can get their hands on the relevant DNA. At present, such people most certainly can, so long as they bother to check the publicly available list of which gene synthesis companies do the right thing and screen orders -- and by implication, which ones don't.
One would hope that at least some of the companies that don't advertise that they screen are "honeypots" paid by intelligence agencies to catch would-be bioterrorists, but even if most of them are, it's still foolish to let individuals access that kind of destructive power. We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural. Hence, we should build a secure and adaptive system capable of screening all DNA synthesis for known and potential future pandemic agents... without disclosing what we think is a credible bioweapon.
Whether or not it becomes a global pandemic, the emergence of Wuhan coronavirus has underscored the need for coordinated action to prevent the spread of pandemic disease. Let's ensure that our reactive response minimally prepares us for future threats, for one day, reacting may not be enough.