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.
Biohackers Made a Cheap and Effective Home Covid Test -- But No One Is Allowed to Use It
Last summer, when fast and cheap Covid tests were in high demand and governments were struggling to manufacture and distribute them, a group of independent scientists working together had a bit of a breakthrough.
Working on the Just One Giant Lab platform, an online community that serves as a kind of clearing house for open science researchers to find each other and work together, they managed to create a simple, one-hour Covid test that anyone could take at home with just a cup of hot water. The group tested it across a network of home and professional laboratories before being listed as a semi-finalist team for the XPrize, a competition that rewards innovative solutions-based projects. Then, the group hit a wall: they couldn't commercialize the test.
They wanted to keep their project open source, making it accessible to people around the world, so they decided to forgo traditional means of intellectual property protection and didn't seek patents. (They couldn't afford lawyers anyway). And, as a loose-knit group that was not supported by a traditional scientific institution, working in community labs and homes around the world, they had no access to resources or financial support for manufacturing or distributing their test at scale.
But without ethical and regulatory approval for clinical testing, manufacture, and distribution, they were legally unable to create field tests for real people, leaving their inexpensive, $16-per-test, innovative product languishing behind, while other, more expensive over-the-counter tests made their way onto the market.
Who Are These Radical Scientists?
Independent, decentralized biomedical research has come of age. Also sometimes called DIYbio, biohacking, or community biology, depending on whom you ask, open research is today a global movement with thousands of members, from scientists with advanced degrees to middle-grade students. Their motivations and interests vary across a wide spectrum, but transparency and accessibility are key to the ethos of the movement. Teams are agile, focused on shoestring-budget R&D, and aim to disrupt business as usual in the ivory towers of the scientific establishment.
Ethics oversight is critical to ensuring that research is conducted responsibly, even by biohackers.
Initiatives developed within the community, such as Open Insulin, which hopes to engineer processes for affordable, small-batch insulin production, "Slybera," a provocative attempt to reverse engineer a $1 million dollar gene therapy, and the hundreds of projects posted on the collaboration platform Just One Giant Lab during the pandemic, all have one thing in common: to pursue testing in humans, they need an ethics oversight mechanism.
These groups, most of which operate collaboratively in community labs, homes, and online, recognize that some sort of oversight or guidance is useful—and that it's the right thing to do.
But also, and perhaps more immediately, they need it because federal rules require ethics oversight of any biomedical research that's headed in the direction of the consumer market. In addition, some individuals engaged in this work do want to publish their research in traditional scientific journals, which—you guessed it—also require that research has undergone an ethics evaluation. Ethics oversight is critical to ensuring that research is conducted responsibly, even by biohackers.
Bridging the Ethics Gap
The problem is that traditional oversight mechanisms, such as institutional review boards at government or academic research institutions, as well as the private boards utilized by pharmaceutical companies, are not accessible to most independent researchers. Traditional review boards are either closed to the public, or charge fees that are out of reach for many citizen science initiatives. This has created an "ethics gap" in nontraditional scientific research.
Biohackers are seen in some ways as the direct descendents of "white hat" computer hackers, or those focused on calling out security holes and contributing solutions to technical problems within self-regulating communities. In the case of health and biotechnology, those problems include both the absence of treatments and the availability of only expensive treatments for certain conditions. As the DIYbio community grows, there needs to be a way to provide assurance that, when the work is successful, the public is able to benefit from it eventually. The team that developed the one-hour Covid test found a potential commercial partner and so might well overcome the oversight hurdle, but it's been 14 months since they developed the test--and counting.
In short, without some kind of oversight mechanism for the work of independent biomedical researchers, the solutions they innovate will never have the opportunity to reach consumers.
In a new paper in the journal Citizen Science: Theory & Practice, we consider the issue of the ethics gap and ask whether ethics oversight is something nontraditional researchers want, and if so, what forms it might take. Given that individuals within these communities sometimes vehemently disagree with each other, is consensus on these questions even possible?
We learned that there is no "one size fits all" solution for ethics oversight of nontraditional research. Rather, the appropriateness of any oversight model will depend on each initiative's objectives, needs, risks, and constraints.
We also learned that nontraditional researchers are generally willing (and in some cases eager) to engage with traditional scientific, legal, and bioethics experts on ethics, safety, and related questions.
We suggest that these experts make themselves available to help nontraditional researchers build infrastructure for ethics self-governance and identify when it might be necessary to seek outside assistance.
Independent biomedical research has promise, but like any emerging science, it poses novel ethical questions and challenges. Existing research ethics and oversight frameworks may not be well-suited to answer them in every context, so we need to think outside the box about what we can create for the future. That process should begin by talking to independent biomedical researchers about their activities, priorities, and concerns with an eye to understanding how best to support them.
Christi Guerrini, JD, MPH studies biomedical citizen science and is an Associate Professor at Baylor College of Medicine. Alex Pearlman, MA, is a science journalist and bioethicist who writes about emerging issues in biotechnology. They have recently launched outlawbio.org, a place for discussion about nontraditional research.
Sept. 13th Event: Delta, Vaccines, and Breakthrough Infections
This virtual event will convene leading scientific and medical experts to address the public's questions and concerns about COVID-19 vaccines, Delta, and breakthrough infections. Audience Q&A will follow the panel discussion. Your questions can be submitted in advance at the registration link.
DATE:
Monday, September 13th, 2021
12:30 p.m. - 1:45 p.m. EDT
REGISTER:
Dr. Amesh Adalja, M.D., FIDSA, Senior Scholar, Johns Hopkins Center for Health Security; Adjunct Assistant Professor, Johns Hopkins Bloomberg School of Public Health; Affiliate of the Johns Hopkins Center for Global Health. His work is focused on emerging infectious disease, pandemic preparedness, and biosecurity.
Dr. Nahid Bhadelia, M.D., MALD, Founding Director, Boston University Center for Emerging Infectious Diseases Policy and Research (CEID); Associate Director, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University; Associate Professor, Section of Infectious Diseases, Boston University School of Medicine. She is an internationally recognized leader in highly communicable and emerging infectious diseases (EIDs) with clinical, field, academic, and policy experience in pandemic preparedness.
Dr. Akiko Iwasaki, Ph.D., Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology and Professor of Epidemiology (Microbial Diseases), Yale School of Medicine; Investigator, Howard Hughes Medical Institute. Her laboratory researches how innate recognition of viral infections lead to the generation of adaptive immunity, and how adaptive immunity mediates protection against subsequent viral challenge.
Dr. Marion Pepper, Ph.D., Associate Professor, Department of Immunology, University of Washington. Her lab studies how cells of the adaptive immune system, called CD4+ T cells and B cells, form immunological memory by visualizing their differentiation, retention, and function.
This event is the third of a four-part series co-hosted by Leaps.org, the Aspen Institute Science & Society Program, and the Sabin–Aspen Vaccine Science & Policy Group, with generous support from the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute.
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.