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.
At the “Apple Store of Doctor’s Offices,” Preventive Care Is High Tech. Is it Worth $150 a Month?
What if going to the doctor's office could be … nice?
If you didn't have to wait for your appointment, but were ushered right in; if your medical data was all collated and easily searchable on an iPhone app; if a remote scribe took notes while you spoke with your doctor so you could make eye contact with them; if your doctor didn't seem horribly rushed.
Would you go to the doctor to get help staying healthy, rather than just to stop being sick?
Would that change the way you thought about your health? Would you go to the doctor to get help staying healthy, rather than just to stop being sick? And would that, in the long run, be much better for you?
Those are the animating questions for Forward, a healthcare startup devoted to preventive care. Led by founder Adrian Aoun, formerly of Google/Sidewalk labs, Forward opened its first office in San Francisco in 2016 and has since expanded to Los Angeles, Orange County, New York, and Washington, D.C., with a San Diego location opening soon.
It's been described as the "Apple Store of doctor's offices," which in some ways is a reaction to Forward's vibe: Patients have described the offices as having blonde wood, minimalist design, sparkling water on tap — and lots of high-tech gadgets, like the full-body scanner that replaces the standard scale and stethoscope.
The interior of a Forward office.
(Courtesy Forward)
The more crucial difference, though, is its model of care. Forward doesn't take insurance. Instead, patients, or "members," pay a flat $149 per month, along the lines of a subscription service like Netflix or a gym membership. That fee covers visits, messaging with medical staff through the Forward app, the use of a wearable (like a Fitbit or a sleep tracker) if the physician recommends it, plus any bloodwork or diagnostic tests run in the on-site labs. (The company declined to disclose how many people have signed up for memberships.)
Predictability is Forward's other significant, distinguishing feature: No surprise co-pays, or extra charges showing up on a billing statement months later. Everything is wrapped up in the $149 membership fee, unless the physician recommends visiting an outside specialist.
That caveat isn't a small one. It's important to note that Forward is in no way meant to replace standard health insurance. The service is strictly focused on preventive care, so it wouldn't be much use in case of an emergency; it's meant to help people, as far as is possible, avoid that emergency at all.
Ani Okkasian's family recently went through such an emergency. Her 62-year-old father, an active and seemingly healthy man living with diabetes, had been feeling unwell for a while, but struggled to receive constructive follow-up or tests from his doctor. It finally emerged that his liver was severely damaged, and he suffered a stroke — the risk of which can be elevated by liver disease. He seemed to deteriorate completely within mere weeks, Okkasian said, and in January he passed away.
"He was someone who'd go to the doctor regularly and listen to what they said and follow it," Okkasian said. "I shouldn't have had to bury my father at 62. I still believe to my core that his death could have been avoided if the primary care was adequate."
"I could tell that the people who designed [Forward] had lost someone to the legacy system; it was so streamlined and so much clearer."
Okkasian began researching, looking for a better alternative, and discovered Forward. Founder Aoun lost his grandfather to a heart attack; his brother's heart attack at age 31 was the impetus to start Forward.
"I could tell that that was the genesis," Okkasian said. "Having just lost someone, and having had to deal with different aspects of the healthcare industry — how complicated and convoluted that all is — I could tell that the people who designed [Forward] had lost someone to the legacy system; it was so streamlined and so much clearer."
So Who Is Forward For?
The Affordable Care Act mandates that evidence-based preventive care must be covered by insurers without any cost to the patient. Today, 30 million Americans are still living without health insurance; but for most of the population, cost shouldn't prevent access to standard, preventive care, says Benjamin Sommers, a physician and professor at the Harvard T.H. Chan School of Public Health who has studied the effect of the ACA on preventive care access.
For Okkasian and her family, it wasn't a lack of access to primary care that was at issue; it was the quality of that primary care. In 2019, that's probably true for a lot of people.
"How come all other industries have been disturbed except the medical industry?" Okkasian asked. "It's disturbing the most people. We're so advanced in so many ways, but when it comes to the healthcare system, we're not prioritizing the wellness of a person."
Is Forward the answer? Well, probably not for everyone. Its office are only in a handful of cities, and there are limits to how scalable it would be; it's unavoidable that the $149 per month charge restricts access for a lot of people. Those who have insurance through their employer might have a flexible spending account (FSA) that would cover some or all of the membership fee, and Forward has said that 15 percent of their early members came from underserved communities and were offered free plans; but for many others, that's just an unworkable extra cost.
Sommers also sounded a dubious note about a maximalist attitude toward data collection.
"Even though some patients may think that 'more is always better' — more testing, more screening, etc. — this isn't true," he said. "Some types of cancer screening, ovarian cancer screening for instance, are actually harmful or of no benefit, because studies have shown that they don't improve survival or health outcomes, but can lead to unnecessary testing, pain, false positives, anxiety, and other side effects.
"It's really great for people who are in good health, looking to make it better."
"I'm generally skeptical of efforts to charge people more to get 'extra testing' that isn't currently supported by the medical evidence," he added.
But relatively healthy people who want to take a more active approach to their health — or people who have frequent testing needs, like those using the HIV-prevention drug PrEP, and want to avoid co-pays — might benefit from the on-demand, low-friction experience that Forward offers.
"It's really great for people who are in good health, looking to make it better," Okkasian said. "Your experience is simplified to a point where you feel empowered, not scared."
Facial Recognition Can Reduce Racial Profiling and False Arrests
[Editor's Note: This essay is in response to our current Big Question, which we posed to experts with different perspectives: "Do you think the use of facial recognition technology by the police or government should be banned? If so, why? If not, what limits, if any, should be placed on its use?"]
Opposing facial recognition technology has become an article of faith for civil libertarians. Many who supported the bans in cities like San Francisco and Oakland have declared the technology to be inherently racist and abusive.
The greatest danger would be to categorically oppose this technology and pretend that it will simply go away.
I have spent my career as a criminal defense attorney and a civil libertarian -- and I do not fear it. Indeed, I see it as positive so long as it is appropriately regulated and controlled.
We are living in the beginning of a biometric age, where technology uses our physical or biological characteristics for a variety of products and services. It holds great promises as well as great risks. The greatest danger, however, would be to categorically oppose this technology and pretend that it will simply go away.
This is an age driven as much by consumer as it is government demand. Living in denial may be emotionally appealing, but it will only hasten the creation of post-privacy world. If we do not address this emerging technology, movements in public will increasingly result in instant recognition and even tracking. It is the type of fish-bowl society that strips away any expectation of privacy in our interactions and associations.
The biometrics field is expanding exponentially, largely due to the popularity of consumer products using facial recognition technology (FRT) -- from the iPhone program to shopping ones that recognize customers.
But the privacy community is losing this battle because it is using the privacy rationales and doctrines forged in the earlier electronic surveillance periods. Just as generals are often accused of planning to fight the last war, civil libertarians can sometimes cling to past models despite their decreasing relevance in the current world.
I see FRT as having positive implications that are worth pursuing. When properly used, biometrics can actually enhance privacy interests and even reduce racial profiling by reducing false arrests and the warrantless "patdowns" allowed by the Supreme Court. Bans not only deny police a technology widely used by businesses, but return police to the highly flawed default of "eye balling" suspects -- a system with a considerably higher error rate than top FRT programs.
Officers are often wrong and stop a great number of suspects in the hopes of finding a wanted felon.
A study in Australia showed that passport officers who had taken photographs of subjects in ideal conditions nonetheless experienced high error rates when identifying them shortly afterward, including 14 percent false acceptance rates. Currently, officers stop suspects based on their memory from seeing a photograph days or weeks earlier. They are often wrong and stop a great number of suspects in the hopes of finding a wanted felon. The best FRT programs achieve an astonishing accuracy rate, though real-world implementation has challenges that must be addressed.
One legitimate concern raised in early studies showed higher error rates in recognitions for certain groups, particularly African American women. An MIT study finding that error rate prompted major improvements in the algorithms as well as training changes to greatly reduce the frequency of errors. The issue remains a concern, but there is nothing inherently racist in algorithms. These are a set of computer instructions that isolate and process with the parameters and conditions set by creators.
To be sure, there is room for improvement in some algorithms. Tests performed by the American Civil Liberties Union (ACLU) reportedly showed only an 80 percent accuracy rate in comparing mug shots to pictures of members of Congress when using Amazon's "Rekognition" system. It recently showed the same 80 percent rate in doing the same comparison to members of the California legislators.
However, different algorithms are available with differing levels of performance. Moreover, these products can be set with a lower discrimination level. The fact is that the top algorithms tested by the National Institute of Standards and Technology showed that their accuracy rate is greater than 99 percent.
The greatest threat of biometric technologies is to democratic values.
Assuming a top-performing algorithm is used, the result could be highly beneficial for civil liberties as opposed to the alternative of "eye balling" suspects. Consider the Boston Bombing where police declared a "containment zone" and forced families into the street with their hands in the air.
The suspect, Dzhokhar Tsarnaev, moved around Boston and was ultimately found outside the "containment zone" once authorities abandoned near martial law. He was caught on some surveillance systems but not identified. FRT can help law enforcement avoid time-consuming area searches and the questionable practice of forcing people out of their homes to physically examine them.
If we are to avoid a post-privacy world, we will have to redefine what we are trying to protect and reconceive how we hope to protect it. In my view, the greatest threat of biometric technologies is to democratic values. Authoritarian nations like China have made huge investments into FRT precisely because they know that the threat of recognition in public deters citizens from associating or interacting with protesters or dissidents. Recognition changes conduct. That chilling effect is what we have the worry about the most.
Conventional privacy doctrines do not offer much protection. The very concept of "public privacy" is treated as something of an oxymoron by courts. Public acts and associations are treated as lacking any reasonable expectation of privacy. In the same vein, the right to anonymity is not a strong avenue for protection. We are not living in an anonymous world anymore.
Consumers want products like FaceFind, which link their images with others across social media. They like "frictionless" transactions and authentications using faceprints. Despite the hyperbole in places like San Francisco, civil libertarians will not succeed in getting that cat to walk backwards.
The basis for biometric privacy protection should not be focused on anonymity, but rather obscurity. You will be increasingly subject to transparency-forcing technology, but we can legislatively mandate ways of obscuring that information. That is the objective of the Biometric Privacy Act that I have proposed in recent research. However, no such comprehensive legislation has passed through Congress.
The ability to spot fraudulent entries at airports or recognizing a felon in flight has obvious benefits for all citizens.
We also need to recognize that FRT has many beneficial uses. Biometric guns can reduce accidents and criminals' conduct. New authentications using FRT and other biometric programs could reduce identity theft.
And, yes, FRT could help protect against unnecessary police stops or false arrests. Finally, and not insignificantly, this technology could stop serious crimes, from terrorist attacks to the capturing of dangerous felons. The ability to spot fraudulent entries at airports or recognizing a felon in flight has obvious benefits for all citizens.
We can live and thrive in a biometric era. However, we will need to bring together civil libertarians with business and government experts if we are going to control this technology rather than have it control us.
[Editor's Note: Read the opposite perspective here.]