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.
What's the case-fatality rate?
Currently, the official rate is 3.4%. But this is likely way too high. China was hit particularly hard, and their healthcare system was overwhelmed. The best data we have is from South Korea. The Koreans tested 210,000 people and detected the virus in 7,478 patients. So far, the death toll is 53, which is a case-fatality rate of 0.7%. This is seven times worse than the seasonal flu (which has a case-fatality rate of 0.1%).
What's the best way to clean your hands? Soap and water? Hand sanitizer?
Soap and water is always best. Be sure to wash your hands thoroughly. (The CDC recommends 20 seconds.) If soap and water are not available, the CDC says to use hand sanitizer that is at least 60% alcohol. The problem with hand sanitizer, however, is that people neither use enough nor spread it over their hands properly. Also, the sanitizer should be covering your hands for 10-15 seconds, not evaporating before that.
How often should I wash my hands?
You should wash your hands after being in a public place, before you eat, and before you touch your face. It's a good idea to wash your hands after handling money and your cell phone, too.
How long can coronavirus live on surfaces?
It depends on the surface. According to the New York Times, "[C]old and flu viruses survive longer on inanimate surfaces that are nonporous, like metal, plastic and wood, and less on porous surfaces, like clothing, paper and tissue." According to the Journal of Hospital Infection, human coronaviruses "can persist on inanimate surfaces like metal, glass or plastic for up to 9 days, but can be efficiently inactivated by surface disinfection procedures with 62–71% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute." (Note: Sodium hypochlorite is bleach.)
Can Lysol wipes kill it?
Maybe not. It depends on the active ingredient. Many Lysol products use benzalkonium chloride, which the aforementioned Journal of Hospital Infection paper said was "less effective." The EPA has released a list of disinfectants recommended for use against coronavirus.
Should you wear a mask in public?
The CDC does not recommend that healthy people wear a mask in public. The benefit is likely small. However, if you are sick, then you should wear a mask to help catch respiratory droplets as you exhale.
Will pets give it to you?
That can't be ruled out. There is a documented case of human-to-canine transmission. However, an article in LiveScience explains that canine-to-human is unlikely.
Are there any "normal" things we are doing that make things worse?
Yes! Not washing your hands!!
What does it mean that previously cleared people are getting sick again? Is it the virus within or have they caught it via contamination?
It's not entirely clear. It could be that the virus was never cleared to begin with. Or it could be that the person was simply infected again. That could happen if the antibodies generated don't last long.
Will the virus go away with the weather/summer?
Quite likely, yes. Cold and flu viruses don't do well outside in summer weather. (For influenza, the warm weather causes the viral envelope to become a liquid, and it can no longer protect the virus.) That's why cold and flu season is always during the late fall and winter. However, some experts think that it is a "false hope" that the coronavirus will disappear during the summer. We'll have to wait and see.
And will it come back in the fall/winter?
That's a likely outcome. Again, we'll have to wait and see. Some epidemiologists think that COVID-19 will become seasonal like influenza.
Does dry or humid air make a difference?
Flu viruses prefer cold, dry weather. That could be true of coronaviruses, too.
What is the incubation period?
According to the World Health Organization, it's about 5 days. But it could be anywhere from 1 to 14 days.
Should you worry about sitting next to asymptomatic people on a plane or train?
It's not possible to tell if an asymptomatic person is infected or not. That's what makes asymptomatic people tricky. Just be cautious. If you're worried, treat everyone like they might be infected. Don't let them get too close or cough in your face. Be sure to wash your hands.
Should you cancel air travel planned in the next 1-2 months in the U.S.?
There are no hard and fast rules. Use common sense. Avoid hotspots of infection. If you have a trip planned to Wuhan, you might want to wait on that one. If you have a trip planned to Seattle and you're over the age of 60 and/or have an underlying health condition, you may want to hold off on that, too. If you do fly on a plane, former FDA commissioner Dr. Scott Gottlieb recommends cleaning the back of your seat and other close contact areas with antiseptic wipes. He also refuses to take anything handed out by flight attendants, since he says the biggest route of transmission comes from touching contaminated surfaces (and then touching your face).
There have been reports of an escalation of hate crimes towards Asian Americans. Can the microbiologist help illuminate that this disease has impacted all racial groups?
People might be racist, but COVID-19 is not. It can infect anyone. Older people (i.e., 60 years and older) and those with underlying health conditions are most at risk. Interestingly, young people (aged 9 and under) are minimally impacted.
To what extent/if any should toddlers -- who put everything in mouth -- avoid group classes like Gymboree?
If they get infected, toddlers will probably experience only a mild illness. The problem is if the toddler then infects somebody at higher risk, like grandpa or grandma.
Should I avoid events like concerts or theater performances if I live in a place where there is known coronavirus?
It's not an unreasonable thing to do.
Any special advice or concerns for pregnant women?
There isn't good data on this. Previous evidence, reported by the CDC, suggests that pregnant women may be more susceptible to respiratory viruses.
Advice for residents of long-term care facilities/nursing homes?
Remind the nurse or aide to constantly wash their hands.
Can we eat at Chinese restaurants? Does eating onions kill viruses? Can I take an Uber and be safe from infection?
Yes. No. Does the Uber driver or previous passengers have coronavirus? It's not possible to tell. So, treat an Uber like a public space and behave accordingly.
What public spaces should we avoid?
That's hard to say. Some people avoid large gatherings, others avoid leaving the house. Ultimately, it's going to depend on who you are and what sort of risk you're willing to take. (For example, are you young and healthy or old and sick?) I would be willing to do things that I would advise older people avoid, like going to a sporting event.
What are the differences between the L strain and the S strain?
That's not entirely clear, and it's not even clear that they are separate strains. There are some genetic differences between them. However, just because RNA viruses mutate doesn't necessarily mean that the virus will mutate to something more dangerous or unrecognizable by our immune system. The measles virus mutates, but it more or less remains the same, which is why a single vaccine could eradicate it – if enough people actually were willing to get a measles shot.
Should I wear disposable gloves while traveling?
No. If you touch something that's contaminated, the virus will be on your glove instead of your hand. If you then touch your face, you still might get sick.
The Best Coronavirus Experts to Follow on Twitter
As the coronavirus tears across the globe, the world's anxiety is at a fever-pitch, and we're all craving information to stay on top of the crisis.
But turning to the Internet for credible updates isn't as simple as it sounds, since we have an invisible foe spreading as quickly as the virus itself: misinformation. From wild conspiracy theories to baseless rumors, an infodemic is in full swing.
For the latest official information, you should follow the CDC, WHO, and FDA, in addition to your local public health department. But it's also helpful to pay attention to the scientists, doctors, public health experts and journalists who are sharing their perspectives in real time as new developments unfold. Here's a handy guide to get you started:
VIROLOGY
Dr. Trevor Bedford/@trvrb: Scientist at the Fred Hutchinson Cancer Research Center studying viruses, evolution and immunity.
Dr. Benhur Lee/@VirusWhisperer: Professor of microbiology at the Icahn School of Medicine at Mount Sinai
Dr. Angela Rasmussen/@angie_rasmussen: Virologist and associate research scientist at Columbia University
Dr. Florian Krammer/@florian_krammer: Professor of Microbiology at the Icahn School of Medicine at Mount Sinai
EPIDEMIOLOGY:
Dr. Alice Sim/@alicesim: Infectious disease epidemiologist and consultant at the World Health Organization
Dr. Tara C. Smith/@aetiology: Infectious disease specialist and professor at Kent State University
Dr. Caitlin Rivers/@cmyeaton: Epidemiologist and assistant professor at the Johns Hopkins Bloomberg School of Public Health
Dr. Michael Mina/@michaelmina_lab: Physician and Assistant Professor of Epidemiology & Immunology at the Harvard TH Chan School of Public Health
INFECTIOUS DISEASE:
Dr. Nahid Bhadelia/@BhadeliaMD: Infectious diseases physician and the medical director of Special Pathogens Unit at Boston University School of Medicine
Dr. Paul Sax/@PaulSaxMD: Clinical Director of the Division of Infectious Diseases at Brigham and Women's Hospital
Dr. Priya Sampathkumar/@PsampathkumarMD: Infectious Disease Specialist at the Mayo Clinic
Dr. Krutika Kuppalli/@KrutikaKuppalli: Medical doctor and Infectious Disease Specialist based in Palo Alto, CA
PANDEMIC PREP:
Dr. Syra Madad/@syramadad: Senior Director, System-wide Special Pathogens Program at New York City Health + Hospitals
Dr Sylvie Briand/@SCBriand: Director of Pandemic and Epidemic Diseases Department at the World Health Organization
Jeremy Konyndyk/@JeremyKonyndyk: Senior Policy Fellow at the Center for Global Development
Amesh Adalja/@AmeshAA: Senior Scholar at the Johns Hopkins University Center for Health Security
PUBLIC HEALTH:
Scott Becker/@scottjbecker: CEO of the Association of Public Health Laboratories
Dr. Scott Gottlieb/@ScottGottliebMD: Physician, former commissioner of the Food and Drug Administration
APHA Public Health Nursing/@APHAPHN: Public Health Nursing Section of the American Public Health Association
Dr. Tom Inglesby/@T_Inglesby: Director of the Johns Hopkins SPH Center for Health Security
Dr. Nancy Messonnier/@DrNancyM_CDC: Director of the Center for the National Center for Immunization and Respiratory Diseases (NCIRD)
Dr. Arthur Caplan/@ArthurCaplan: Professor of Bioethics at New York University Langone Medical Center
SCIENCE JOURNALISTS:
Laura Helmuth/@laurahelmuth: Incoming Editor in Chief of Scientific American
Helen Branswell/@HelenBranswell: Infectious disease and public health reporter at STAT
Sharon Begley/@sxbegle: Senior writer at STAT
Carolyn Johnson/@carolynyjohnson: Science reporter at the Washington Post
Amy Maxmen/@amymaxmen: Science writer and senior reporter at Nature
Laurie Garrett/@Laurie_Garrett: Pulitzer-prize winning science journalist, author of The Coming Plague, former senior fellow for global health at the Council on Foreign Relations
Soumya Karlamangla/@skarlamangla: Health writer at the Los Angeles Times
André Picard/@picardonhealth: Health Columnist, The Globe and Mail
Caroline Chen/@CarolineYLChen: Healthcare reporter at ProPublica
Andrew Jacobs/@AndrewJacobsNYT: Science reporter at the New York Times
Meg Tirrell/@megtirrell: Biotech and pharma reporter for CNBC
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.