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.
In October 2006, Craig Mello received a strange phone call from Sweden at 4:30 a.m. The voice at the other end of the line told him to get dressed and that his life was about to change.
"We think this could be effective in [the early] phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Shortly afterwards, he was informed that along with his colleague Andrew Fire, he had won the Nobel Prize in Physiology or Medicine.
Eight years earlier, biologists Fire and Mello had made a landmark discovery in the history of genetics. In a series of experiments conducted in worms, they had revealed an ancient evolutionary mechanism present in all animals that allows RNA – the structures within our cells that take genetic information from DNA and use it to make proteins – to selectively switch off genes.
At the time, scientists heralded the dawn of a new field of medical research utilizing this mechanism, known as RNA interference or RNAi, to tackle rare genetic diseases and deactivate viruses. Now, 14 years later, the pharmaceutical company Alnylam — which has pioneered the development of RNAi-based treatments over the past decade — is looking to use it to develop a groundbreaking drug for the virus that causes COVID-19.
"We can design small interfering RNAs to target regions of the viral genome and bind to them," said Akin Akinc, who manages several of Alnylam's drug development programs. "What we're learning about COVID-19 is that there's an early phase where there's lots of viral replication and a high viral load. We think this could be effective in that phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Called ALN-COV, Alnylam's treatment hypothetically works by switching off a key gene in the virus, inhibiting its ability to replicate itself. In order to deliver it to the epithelial cells deep in the lung tissue, where the virus resides, patients will inhale a fine mist containing the RNAi molecules mixed in a saline solution, using a nebulizer.
But before human trials of the drug can begin, the company needs to convince regulators that it is both safe and effective in a series of preclinical trials. While early results appear promising - when mixed with the virus in a test tube, the drug displayed a 95 percent inhibition rate – experts are reserving judgment until it performs in clinical trials.
"If successful this could be a very important milestone in the development of RNAi therapies, but virus infections are very complicated and it can be hard to predict whether a given level of inhibition in cell culture will be sufficient to have a significant impact on the course of the infection," said Si-Ping Han, who researches RNAi therapeutics at California Institute of Technology and is not involved in the development of this drug.
So far, Alnylam has had success in using RNAi to treat rare genetic diseases. It currently has treatments licensed for Hereditary ATTR Amyloidosis and Acute Hepatic Porphyria. Another treatment, for Primary Hyperoxaluria Type 1, is currently under regulatory review. But its only previous attempt to use RNAi to tackle a respiratory infection was a failed effort to develop a drug for respiratory syncytial virus (RSV) almost a decade ago.
However, the technology has advanced considerably since then. "Back then, RNAi drugs had no chemical modifications whatsoever, so they were readily degraded by the body, and they could also result in unintended immune stimulation," said Akinc. "Since then, we've learned how to chemically modify our RNAi's to make them immunosilent and give them improved potency, stability, and duration of action."
"It would be a very important milestone in the development of RNAi therapies."
But one key challenge the company will face is the sheer speed at which viruses evolve, meaning they can become drug-resistant very quickly. Scientists predict that Alnylam will ultimately have to develop a series of RNAi drugs for the coronavirus that work together.
"There's been considerable interest in using RNAi to treat viral infections, as RNA therapies can be developed more rapidly than protein therapies like monoclonal antibodies, since one only needs to know the viral genome sequence to begin to design them," said David Schaffer, professor of bioengineering at University of California, Berkeley. "But viruses can evolve their sequences rapidly around single drugs so it is likely that a combinatorial RNAi therapy may be needed."
In the meantime, Alnylam is conducting further preclinical trials over the summer and fall, with the aim of launching testing in human volunteers by the end of this year -- an ambitious aim that would represent a breakneck pace for a drug development program.
If the approach does ultimately succeed, it would represent a major breakthrough for the field as a whole, potentially opening the door to a whole new wave of RNAi treatments for different lung infections and diseases.
"It would be a very important milestone in the development of RNAi therapies," said Han, the Caltech researcher. "It would be both the first time that an RNAi drug has been successfully used to treat a respiratory infection and as far as I know, the first time that one has been successful in treating any disease in the lungs. RNAi is a platform that can be reconfigured to hit different targets, and so once the first drug has been developed, we can expect a rapid flow of variants targeting other respiratory infections or other lung diseases."
The Biggest Challenge for a COVID-19 Vaccine
Although no one has conducted a survey on the topic, it's safe to say that a single hope unites much of humanity at the present moment: the prospect of a vaccine for COVID-19, which has infected more than 9 million people worldwide, killed nearly 500,000, and sent the global economy into a tailspin since it first appeared in China last December.
"We've never delivered something to every corner of the world before."
Scientists are racing to make that vision a reality. As of this writing, 11 vaccine candidates are in clinical trials and over 100 others are in preclinical development, in a dozen countries. Pointing to new technology and compressed testing protocols, experts predict a winner could emerge in 12 to 18 months—a fraction of the four years it took to develop the previous record-holder, the mumps vaccine, in the 1960s. Teams at Oxford University and Boston-based Moderna Therapeutics say they could have a product ready even sooner, if the formulas they're testing prove safe and effective. A just-announced White House initiative, Operation Warp Speed, aims to fast-track multiple candidates, with the goal of delivering 100 million doses in November and another 200 million by January 2021.
These timetables could prove wildly over-optimistic. But even if the best-case scenario comes true, and a viable COVID-19 vaccine emerges this fall, a gargantuan challenge remains: getting the shot to everyone who needs it. Epidemiologists figure that at least 70 percent of Earth's population—or 5.6 billion people—would have to be inoculated to achieve "herd immunity," in which each person who catches the disease passes it to less than one other individual. "In order to stop the pandemic, we need to make the vaccine available to almost every person on the planet," Microsoft co-founder Bill Gates blogged in April, as his foundation pledged $300 million to the effort. "We've never delivered something to every corner of the world before."
The difficulties are partly logistical, partly political, and largely a combination of the two. Overcoming those obstacles will require unprecedented cooperation among national governments, international organizations, and profit-minded corporations—in an era when nationalist rivalries are rampant and global leadership is up for grabs.
That may be tougher than developing the vaccine itself.
Logistical Conundrums
Manufacturing and distributing billions of vaccine doses would be a daunting task even in the most harmonious of times. Take the packaging problem. The vaccines under development range from old-school (based on inactivated or weakened viruses) to cutting-edge (using snippets of RNA or DNA to train the immune system to attack the invader). Some may work better than others for different patient groups—the young versus the elderly, for example. All, however, must be stored in vials and administered with syringes.
Among the handful of U.S. companies that manufacture such products, many must import the special glass tubing for vials, as well as the polypropylene for syringe barrels and the rubber or silicone for stoppers and plungers. These materials are commonly sourced from China and India, where lockdowns and export bans restrict supply. Rick Bright, the ousted director of the federal Biomedical Advanced Research and Development Authority (BARDA), claims he was ignored when he warned the Trump Administration that a medical-glass shortage was looming before the coronavirus crisis hit; securing enough to vaccinate 300 million Americans, he told Congress in May, could take up to two years.
Getting the vaccine to poorer countries presents further hurdles. To begin with, there's refrigeration. Inactivated or live vaccines must be kept between 2 and 8 degrees Centigrade (or 35 to 46 degrees Fahrenheit); RNA vaccines typically require much colder temperatures—as low as -80 degrees. This makes storage and transport challenging in parts of the world that lack reliable electricity. DNA vaccines don't need cold storage, but (like RNA vaccines) they remain experimental. They've never been approved to treat any human disease.
Tracking vaccine distribution is another conundrum for low- to-middle-income countries. "Supply chain management is really about information," explains Rebecca Weintraub, assistant professor of global health and social medicine at Harvard Medical School and director of the Better Evidence project at Harvard's Ariadne Labs. "It's about leveraging data to determine demand, predict behavior, and understand the flow of the product itself." Systems for collecting and analyzing such data can be hard to find in poorer regions, she notes. What's more, many people in those areas lack any type of ID card, making it difficult to know who has or hasn't received a vaccine.
Weintraub and two coauthors published an article in April in the Harvard Business Review, suggesting solutions to these and other developing-world problems: solar direct-drive refrigerators, app-based data-capture systems, biometric digital IDs. But such measures—not to mention purchasing adequate supplies of vaccine—would require massive funding.
And that's where the logistical begins to overlap with the political.
Global Access Versus "Vaccine Nationalism"
An array of institutions have already begun laying the groundwork for achieving worldwide, equitable access to COVID-19 vaccines. In February, the World Bank and the Norway-based Coalition for Epidemic Preparedness Innovations (CEPI) cohosted a global consultation on funding vaccine development and manufacturing. In late April, the World Health Organization (WHO), in collaboration with dozens of governments, nonprofits, and industry leaders, launched a program called the Access to COVID-19 Tools Accelerator to expedite such efforts.
Soon afterward, the European Union, along with six countries and the Bill and Melinda Gates Foundation, held a Coronavirus Global Response telethon that raised $8 billion to support Gavi, the Vaccine Alliance—a public-private partnership that subsidizes immunization in low-income countries. The United States and Russia, however, chose not to participate.
This snub by the world's remaining superpower and one of its principal challengers worried many observers. "I am concerned about what I call vaccine nationalism," CEPI executive director Richard Hatchett told the Los Angeles Times. "That's the tension between obligations elected leaders will feel to protect the lives of their citizens" versus the imperative for global sharing.
Some signs point to a possible rerun of the hoarding that accompanied the 2009 H1N1 influenza pandemic, when wealthy nations bought up virtually all vaccine supplies—denying them to poorer countries, and sometimes to one another. Operation Warp Speed has declared an "America First" policy for any vaccine arising from its efforts. Pharma giant Sanofi recently suggested that it would take a similar approach, since the U.S. was first to fund the company's COVID-19 research. (Sanofi's CEO backtracked after officials in France, where the firm is headquartered, protested.) The Oxford group, which is partnering with British-based drug maker AstraZeneca, intends to prioritize Great Britain.
Yet momentum is building for more generous strategies as well. In May, over 100 current and former world leaders, along with prominent economists and public health experts, issued an open letter calling for a "people's vaccine" for COVID-19, which would be patent-free, distributed globally, and available to all countries free of charge. At the WHO's annual World Health Assembly, all 194 member states accepted a resolution urging that vaccines for the disease be made available as a "global public good"—though the U.S. dissociated itself from a clause proposing a patent pool to keep costs down, which it argued might disincentivize "innovators who will be essential to the solutions the whole world needs."
Gavi, for its part, plans to launch a mechanism designed to encourage those innovators while promoting accessibility: an advance market commitment, in which countries pledge to purchase a vaccine, with no money down. Future contributions will be based on the value of the product to their health systems and their ability to pay.
"It's essential to realize that a threat anywhere is a threat everywhere."
A few private-sector players are stepping up, too. U.S.-based Johnson & Johnson, which has received nearly half a billion dollars from the federal government for COVID-19 vaccine research, has promised to provide up to 900 million doses on a not-for-profit basis, if its trials pan out. Other companies have agreed to produce vaccines on a "cost-plus" basis, with a smaller-than-usual profit margin.
How Sharing Can Pay Off
No one knows how all this will work out if and when a vaccine becomes available. (Another wild card: Trump has announced that he is cutting U.S. ties to the WHO over its alleged favoritism toward China, which could hobble the agency's ability to coordinate distribution -- though uncertainty remains about the process of withdrawal and reversing course may still be possible.) To public health experts, however, it's clear that ensuring accessibility is not just a matter of altruism.
"A historic example is smallpox," Rebecca Weintraub observes. "When it kept getting reintroduced into high-income countries from low-income countries, the rich countries realized it was worth investing in the vaccine for countries that couldn't afford it." After a two-decade campaign led by the WHO, the last case of this ancient scourge was diagnosed in 1977.
Conversely, vaccine nationalism doesn't just hurt poor countries. During the H1N1 pandemic, which killed an estimated 284,000 people worldwide, production problems led to shortages in the United States. But Australia stopped a domestic manufacturer from exporting doses to the U.S until all Aussies had been immunized.
Such considerations, Weintraub believes, might help convince even the most reluctant rich-country leaders that an accessible vaccine—if deployed in an epidemiologically targeted way—would serve both the greater good and the national interest. "I suspect the pressures put on our politicians to act globally will be significant," she says.
Other analysts share her guarded optimism. Kelly Moore, who teaches health policy at Vanderbilt University Medical Center, oversaw Tennessee's immunization programs for more than a decade, and later became a member of the Sabin-Aspen Vaccine Science & Policy Group—a panel of international experts that in 2019 released a report titled "Accelerating the Development of a Universal Influenza Vaccine." The 117-page document provided a road map toward a long-sought goal: creating a flu shot that doesn't need to be reformulated each year to target changing viral strains.
"One lesson we learned was that it's crucial to deploy financial resources in a systematic way to support coordination among laboratories that would typically be competitors," Moore says. And that, she adds, is happening with COVID-19, despite nationalist frictions: scientists from Sanofi joining forces with those at rival GSK; researchers at other companies allying with teams at government laboratories; university labs worldwide sharing data across borders. "I have been greatly encouraged to see the amount of global collaboration involved in this enterprise. Partners are working together who would normally never be partners."
For Moore, whose 77-year-old mother survived a bout with the disease, the current pandemic has hit close to home. "It's essential to realize that a threat anywhere is a threat everywhere," she says. "Morally and ethically, we have a tremendous obligation to ensure that the most vulnerable have access to an affordable vaccine, irrespective of where they live."
[Editor's Note: 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. For this reprinting of the article, we have updated the latest statistics on COVID-19 and related global news.]
CORRECTION: A sentence about DNA vaccines incorrectly stated that they require cold storage, like RNA vaccines. The error has been fixed.