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.
Will the Pandemic Propel STEM Experts to Political Power?
If your car won't run, you head to a mechanic. If your faucet leaks, you contact a plumber. But what do you do if your politics are broken? You call a… lawyer.
"Scientists have been more engaged with politics over the past three years amid a consistent sidelining of science and expertise, and now the pandemic has crystalized things even more."
That's been the American way since the beginning. Thousands of members of the House and Senate have been attorneys, along with nearly two dozen U.S. presidents from John Adams to Abraham Lincoln to Barack Obama. But a band of STEM professionals is changing the equation. They're hoping anger over the coronavirus pandemic will turn their expertise into a political superpower that propels more of them into office.
"This could be a turning point, part of an acceleration of something that's already happening," said Nancy Goroff, a New York chemistry professor who's running for a House seat in Long Island and will apparently be the first female scientist with a Ph.D. in Congress. "Scientists have been more engaged with politics over the past three years amid a consistent sidelining of science and expertise, and now the pandemic has crystalized things even more."
Professionals in the science, technology, engineering and medicine (STEM) fields don't have an easy task, however. To succeed, they must find ways to engage with voters instead of their usual target audiences — colleagues, patients and students. And they'll need to beat back a long-standing political tradition that has made federal and state politics a domain of attorneys and businesspeople, not nurses and biologists.
In the 2017-2018 Congress, more members of Congress said they'd worked as radio talk show hosts (seven) and as car dealership owners (six) than scientists (three — a physicist, a microbiologist, and a chemist), according to a 2018 report from the Congressional Research Service. There were more bankers (18) than physicians (14), more management consultants (18) than engineers (11), and more former judges (15) than dentists (4), nurses (2), veterinarians (3), pharmacists (1) and psychologists (3) combined.
In 2018, a "STEM wave" brought nine members with STEM backgrounds into office. But those with initials like PhD, MD and RN after their names are still far outnumbered by Esq. and MBA types.
Why the gap? Astrophysicist Rush Holt Jr., who served from 1999-2015 as a House representative from New Jersey, thinks he knows. "I have this very strong belief, based on 16 years in Congress and a long, intense public life, that the problem is not with science or the scientists," said. "It has to do with the fact that the public just doesn't pay attention to science. It never occurs to them that they have any role in the matter."
But Holt, former chief executive of the American Association for the Advancement of Science, believes change is on the way. "It's likely that the pandemic will affect people's attitudes," former congressman Holt said, "and lead them to think that they need more scientific thinking in policy-making and legislating." Holt's father was a U.S. senator from West Virginia, so he grew up with a political education. But how can scientists and medical professionals succeed if they have no background in the art of wooing voters?
That's where an organization called 314 Action comes in. Named after the first three digits of pi, 314 Action declares itself to be the "pro-science resistance" and says it's trained more than 1,400 scientists to run for public office.
In 2018, 9 out of 13 House and Senate candidates endorsed by the group won their races. In 2020, 314 Action is endorsing 12 candidates for the House (including an engineer), four for the Senate (including an astronaut) and one for governor (a mathematician in Kansas). It expects to spend $10 million-$20 million to support campaigns this year.
"Physicians, scientists and engineers are problem-solvers," said Shaughnessy Naughton, a Pennsylvania chemist who founded 314 Action after an unsuccessful bid for Congress. "They're willing to dive into issues, and their skills would benefit policy decisions that extend way beyond their scientific fields of expertise."
Like many political organizations, 314 Action focuses on teaching potential candidate how to make it in politics, aiming to help them drop habits that fail to bridge the gap between scientists and civilians. "Their first impulse is not to tell a story," public speaking coach Chris Jahnke told the public radio show "Marketplace" in 2018. "They would rather start with a stat." In a training session, Jahnke aimed to teach them to do both effectively.
"It just comes down to being able to speak about general principles in regular English, and to always have the science intertwined with basic human values," said Rep. Kim Schrier, a Washington state pediatrician who won election to Congress in 2018.
She believes her experience on the job has helped her make connections with voters. In a chat with parents about vaccines for their child, for example, she knows not to directly jump into an arcane discussion of case-control studies.
The best alternative, she said, is to "talk about how hard it is to be a parent making these decisions, feeling scared and worried. Then say that you've looked at the data and the research, and point out that pediatricians would never do anything to hurt children because we want to do everything that is good for them. When you speak heart to heart, it gets across the message and the credibility of medicine and science."
The pandemic "will hopefully awaken people and trigger a change that puts science, medicine and public health on a pedestal where science is revered and not dismissed as elitist."
Communication skills will be especially important if the pandemic spurs more Americans to focus on politics and the records of incumbents in regard to matters like public health and climate change. Thousands of candidates will have to address the nation's coronavirus response, and a survey commissioned by 314 Action suggests that voters may be receptive to those with STEM backgrounds. The poll, of 1,002 likely voters in early April 2020, found that 41%-46% of those surveyed said they'd be "much more favorable" toward candidates who were doctors, nurses, scientists and public health professionals. Those numbers were the highest in the survey compared to just 9% for lawyers.
The pandemic "will hopefully awaken people and trigger a change that puts science, medicine and public health on a pedestal where science is revered and not dismissed as elitist," Dr. Schrier said. "It will come from a recognition that what's going to get us out of this bind are scientists, vaccine development and the hard work of the people in public health on the ground."
[This article was originally 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.]
The coronavirus pandemic exposed significant weaknesses in the country's food supply chain. Grocery store meat counters were bare. Transportation interruptions influenced supply. Finding beef, poultry, and pork at the store has been, in some places, as challenging as finding toilet paper.
In traditional agriculture models, it takes at least three months to raise chicken, six to nine months for pigs, and 18 months for cattle.
It wasn't a lack of supply -- millions of animals were in the pipeline.
"There's certainly enough food out there, but it can't get anywhere because of the way our system is set up," said Amy Rowat, an associate professor of integrative biology and physiology at UCLA. "Having a more self-contained, self-sufficient way to produce meat could make the supply chain more robust."
Cultured meat could be one way of making the meat supply chain more resilient despite disruptions due to pandemics such as COVID-19. But is the country ready to embrace lab-grown food?
According to a Good Food Institute study, GenZ is almost twice as likely to embrace meat alternatives for reasons related to social and environmental awareness, even prior to the pandemic. That's because this group wants food choices that reflect their values around food justice, equity, and animal welfare.
Largely, the interest in protein alternatives has been plant-based foods. However, factors directly related to COVID-19 may accelerate consumer interest in the scaling up of cell-grown products, according to Liz Specht, the associate director of science and technology at The Good Food Institute. The latter is a nonprofit organization that supports scientists, investors, and entrepreneurs working to develop food alternatives to conventional animal products.
While lab-grown food isn't ready yet to definitively crisis-proof the food supply chain, experts say it offers promise.
Matching Supply and Demand
Companies developing cell-grown meat claim it can take as few as two months to develop a cell into an edible product, according to Anthony Chow, CFA at Agronomics Limited, an investment company focused on meat alternatives. Tissue is taken from an animal and placed in a culture that contains nutrients and proteins the cells need to grow and expand. He cites a Good Food Institute report that claims a 2.5-millimeter sample can grow three and a half tons of meat in 40 days, allowing for exponential growth when needed.
In traditional agriculture models, it takes at least three months to raise chicken, six to nine months for pigs, and 18 months for cattle. To keep enough maturing animals in the pipeline, farms must plan the number of animals to raise months -- even years -- in advance. Lab-grown meat advocates say that because cultured meat supplies can be flexible, it theoretically allows for scaling up or down in significantly less time.
"Supply and demand has drastically changed in some way around the world and cultivated meat processing would be able to adapt much quicker than conventional farming," Chow said.
Scaling Up
Lab-grown meat may provide an eventual solution, but not in the immediate future, said Paul Mozdziak, a professor of physiology at North Carolina State University who researches animal cell culture techniques, transgenic animal production, and muscle biology.
"The challenge is in culture media," he said. "It's going to take some innovation to get the cells to grow at quantities that are going to be similar to what you can get from an animal. These are questions that everybody in the space is working on."
Chow says some of the most advanced cultured meat companies, such as BlueNal, anticipate introducing products to the market midway through next year. However, he thinks COVID-19 has slowed the process. Once introduced, they will be at a premium price, most likely available at restaurants before they hit grocery store shelves.
"I think in five years' time it will be in a different place," he said. "I don't think that this will have relevance for this pandemic, but certainly beyond that."
"Plant-based meats may be perceived as 'alternatives' to meat, whereas lab-grown meat is producing the same meat, just in a much more efficient manner, without the environmental implications."
Of course, all the technological solutions in the world won't solve the problem unless people are open-minded about embracing them. At least for now, a lab-grown burger or bluefin tuna might still be too strange for many people, especially in the U.S.
For instance, a 2019 article published by "Frontiers in Sustainable Food Systems" reflects results from a study of 3,030 consumers showing that 29 percent of U.S. customers, 59 percent of Chinese consumers, and 56 percent of Indian consumers were either 'very' or 'extremely likely' to try cultivated meat.
"Lab-grown meat is genuine meat, at the cellular level, and therefore will match conventional meat with regard to its nutritional content and overall sensory experience. It could be argued that plant-based meat will never be able to achieve this," says Laura Turner, who works with Chow at Agronomics Limited. "Plant-based meats may be perceived as 'alternatives' to meat, whereas lab-grown meat is producing the same meat, just in a much more efficient manner, without the environmental implications."
A Solution Beyond This Pandemic
The coronavirus has done more than raise awareness of the fragility of food supply chains. It has also been a wakeup call for consumers and policy makers that it is time to radically rethink our meat, Specht says. Those factors have elevated the profile of lab-grown meat.
"I think the economy is getting a little bit more steam and if I was an investor, I would be getting excited about it," adds Mozdziak.
Beyond crises, Mozdziak explains that as affluence continues to increase globally, meat consumption increases exponentially. Yet farm animals can only grow so quickly and traditional farming won't be able to keep up.
"Even Tyson is saying that by 2050, there's not going to be enough capacity in the animal meat space to meet demand," he notes. "If we don't look at some innovative technologies, how are we going to overcome that?"