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.
Blood Money: Paying for Convalescent Plasma to Treat COVID-19
Convalescent plasma – first used to treat diphtheria in 1890 – has been dusted off the shelf to treat COVID-19. Does it work? Should we rely strictly on the altruism of donors or should people be paid for it?
The biologic theory is that a person who has recovered from a disease has chemicals in their blood, most likely antibodies, that contributed to their recovery, and transferring those to a person who is sick might aid their recovery. Whole blood won't work because there are too few antibodies in a single unit of blood and the body can hold only so much of it.
Plasma comprises about 55 percent of whole blood and is what's left once you take out the red blood cells that carry oxygen and the white blood cells of the immune system. Most of it is water but the rest is a complex mix of fats, salts, signaling molecules and proteins produced by the immune system, including antibodies.
A process called apheresis circulates the donors' blood through a machine that separates out the desired parts of blood and returns the rest to the donor. It takes several times the length of a regular whole blood donation to cycle through enough blood for the process. The end product is a yellowish concentration called convalescent plasma.
Recent History
It was used extensively during the great influenza epidemic off 1918 but fell out of favor with the development of antibiotics. Still, whenever a new disease emerges – SARS, MERS, Ebola, even antibiotic-resistant bacteria – doctors turn to convalescent plasma, often as a stopgap until more effective antibiotic and antiviral drugs are developed. The process is certainly safe when standard procedures for handling blood products are followed, and historically it does seem to be beneficial in at least some patients if administered early enough in the disease.
With few good treatment options for COVID-19, doctors have given convalescent plasma to more than a hundred thousand Americans and tens of thousand of people elsewhere, to mixed results. Placebo-controlled trials could give a clearer picture of plasma's value but it is difficult to enroll patients facing possible death when the flip of a coin will determine who will receive a saline solution or plasma.
And the plasma itself isn't some uniform pill stamped out in a factory, it's a natural product that is shaped by the immune history of the donor's body and its encounter not just with SARS-CoV-2 but a lifetime of exposure to different pathogens.
Researchers believe antibodies in plasma are a key factor in directly fighting the virus. But the variety and quantity of antibodies vary from donor to donor, and even over time from the same donor because once the immune system has cleared the virus from the body, it stops putting out antibodies to fight the virus. Often the quality and quantity of antibodies being given to a patient are not measured, making it somewhat hit or miss, which is why several companies have recently developed monoclonal antibodies, a single type of antibody found in blood that is effective against SARS-CoV-2 and that is multiplied in the lab for use as therapy.
Plasma may also contain other unknown factors that contribute to fighting disease, say perhaps signaling molecules that affect gene expression, which might affect the movement of immune cells, their production of antiviral molecules, or the regulation of inflammation. The complexity and lack of standardization makes it difficult to evaluate what might be working or not with a convalescent plasma treatment. Thus researchers are left with few clues about how to make it more effective.
Industrializing Plasma
Many Americans living along the border with Mexico regularly head south to purchase prescription drugs at a significant discount. Less known is the medical traffic the other way, Mexicans who regularly head north to be paid for plasma donations, which are prohibited in their country; the U.S. allows payment for plasma donations but not whole blood. A typical payment is about $35 for a donation but the sudden demand for convalescent plasma from people who have recovered from COVID-19 commands a premium price, sometimes as high as $200. These donors are part of a fast-growing plasma industry that surpassed $25 billion in 2018. The U.S. supplies about three-quarters of the world's needs for plasma.
Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free.
The pharmaceutical industry has shied away from natural products they cannot patent but they have identified simpler components from plasma, such as clotting factors and immunoglobulins, that have been turned into useful drugs from this raw material of plasma. While some companies have retooled to provide convalescent plasma to treat COVID-19, often paying those donors who have recovered a premium of several times the normal rate, most convalescent plasma has come as donations through traditional blood centers.
In April the Mayo Clinic, in cooperation with the FDA, created an expanded access program for convalescent plasma to treat COVID-19. It was meant to reduce the paperwork associated with gaining access to a treatment not yet approved by the FDA for that disease. Initially it was supposed to be for 5000 units but it quickly grew to more than twenty times that size. Michael Joyner, the head of the program, discussed that experience in an extended interview in September.
The Centers for Medicare and Medicaid Services (CMS) also created associated reimbursement codes, which became permanent in August.
Mayo published an analysis of the first 35,000 patients as a preprint in August. It concluded, "The relationships between mortality and both time to plasma transfusion, and antibody levels provide a signature that is consistent with efficacy for the use of convalescent plasma in the treatment of hospitalized COVID-19 patients."
It seemed to work best when given early in infection and in larger doses; a similar pattern has been seen in studies of monoclonal antibodies. A revised version will soon be published in a major medical journal. Some criticized the findings as not being from a randomized clinical trial.
Convalescent plasma is not the only intervention that seems to work better when used earlier in the course of disease. Recently the pharmaceutical company Eli Lilly stopped a clinical trial of a monoclonal antibody in hospitalized COVID-19 patients when it became apparent it wasn't helping. It is continuing trials for patients who are less sick and begin treatment earlier, as well as in persons who have been exposed to the virus but not yet diagnosed as infected, to see if it might prevent infection. In November the FDA eased access to this drug outside of clinical trials, though it is not yet approved for sale.
Show Me the Money
The antibodies that seem to give plasma its curative powers are fragile proteins that the body produces to fight the virus. Production shuts down once the virus is cleared and the remaining antibodies survive only for a few weeks before the levels fade. [Vaccines are used to train immune cells to produce antibodies and other defenses to respond to exposure to future pathogens.] So they can be usefully harvested from a recovered patient for only a few short weeks or months before they decline precipitously. The question becomes, how does one mobilize this resource in that short window of opportunity?
The program run by the Mayo Clinic explains the process and criteria for donating convalescent plasma for COVID-19, as well as links to local blood centers equipped to handle those free donations. Commercial plasma centers also are advertising and paying for donations.
A majority of countries prohibit paying donors for blood or blood products, including India. But an investigation by India Today touted a black market of people willing to donate convalescent plasma for the equivalent of several hundred dollars. Officials vowed to prosecute, saying donations should be selfless.
But that enforcement threat seemed to be undercut when the health minister of the state of Assam declared "plasma donors will get preference in several government schemes including the government job interview." It appeared to be a form of compensation that far surpassed simple cash.
The small city of Rexburg, Idaho, with a population a bit over 50,000, overwhelmingly Mormon and home to a campus of Brigham Young University, at one point had one of the highest per capita rates of COVID-19 in the current wave of infection. Rumors circulated that some students were intentionally trying to become infected so they could later sell their plasma for top dollar, potentially as much as $200 a visit.
Troubled university officials investigated the allegations but could come up with nothing definitive; how does one prove intentionality with such an omnipresent yet elusive virus? They chalked it up to idle chatter, perhaps an urban legend, which might be associated with alcohol use on some other campus.
Doctors, hospitals, and drug companies are all rightly praised for their altruism in the fight against COVID-19, but they also get paid. Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free. "Why do we expect the donors [of convalescent plasma] to be the only uncompensated people in the process? It really makes no sense," argues Mark Yarborough, an ethicist at the UC Davis School of Medicine in Sacramento.
"When I was in grad school, two of my closest friends, at least once a week they went and gave plasma. That was their weekend spending money," Yarborough recalls. He says upper and middle-income people may have the luxury of donating blood products but prohibiting people from selling their plasma is a bit paternalistic and doesn't do anything to improve the economic status of poor people.
"Asking people to dedicate two hours a week for an entire year in exchange for cookies and milk is demonstrably asking too much," says Peter Jaworski, an ethicist who teaches at Georgetown University.
He notes that companies that pay plasma donors have much lower total costs than do operations that rely solely on uncompensated donations. The companies have to spend less to recruit and retain donors because they increase payments to encourage regular repeat donations. They are able to more rationally schedule visits to maximize use of expensive apheresis equipment and medical personnel used for the collection.
It seems that COVID-19 has been with us forever, but in reality it is less than a year. We have learned much over that short time, can now better manage the disease, and have lower mortality rates to prove it. Just how much convalescent plasma may have contributed to that remains an open question. Access to vaccines is months away for many people, and even then some people will continue to get sick. Given the lack of proven treatments, it makes sense to keep plasma as part of the mix, and not close the door to any legitimate means to obtain it.
Vaccines Without Vaccinations Won’t End the Pandemic
COVID-19 vaccine development has advanced at a record-setting pace, thanks to our nation's longstanding support for basic vaccine science coupled with massive public and private sector investments.
Yet, policymakers aren't according anywhere near the same level of priority to investments in the social, behavioral, and data science needed to better understand who and what influences vaccination decision-making. "If we want to be sure vaccines become vaccinations, this is exactly the kind of work that's urgently needed," says Dr. Bruce Gellin, President of Global Immunization at the Sabin Vaccine Institute.
Simply put: it's possible vaccines will remain in refrigerators and not be delivered to the arms of rolled-up sleeves if we don't quickly ramp up vaccine confidence research and broadly disseminate the findings.
According to the most recent Gallup poll, the share of U.S. adults who say they would get a COVID-19 vaccine rose to 58 percent this month from 50 percent in September, with non-white Americans and those ages 45-65 even less willing to be vaccinated. While there is still much we don't understand about COVID-19, we do know that without high levels of immunity in the population, a return to some semblance of normalcy is wishful thinking.
Research from prior vaccination campaigns such as H1N1, HPV, and the annual flu points us in the right direction. Key components of successful vaccination efforts require 1) Identifying the concerns of particular segments of the population; 2) Tailoring messages and incentives to address those concerns, and 3) Reaching out through trusted sources – health care providers, public health departments, and others in the community.
Research during the H1N1 flu found preparing people for some uncertainty actually improved trust, according to Dr. Sandra Crouse Quinn, professor and chair, Family Science, University of Maryland. Dr. Crouse Quinn's research during that period also underscored the need to address the specific vaccine concerns of racial and ethnic groups.
The stunning scientific achievement of COVID-19 vaccines anticipated to be ready in record time needs to be backed up by an equally ambitious and evidence-based effort to build the public's confidence in the vaccines.
Data science has provided crucial insight about the social media universe. Dr. Neil Johnson, a scientist at George Washington University, found that despite having fewer followers, anti-vaccination pages are more numerous and growing faster than pro-vaccination pages. They are more often linked to in discussions on other Facebook pages – such as school parent associations – where people are undecided about vaccination.
We've learned about building vaccine confidence from earlier campaigns. Now, however, we are faced with a unique and challenging set of obstacles to unpack quickly: How do we communicate the importance of eventual COVID-19 vaccines to Americans in light of the muddled-to-poor messaging from political leaders, the weaponizing of relatively simple public health recommendations, the enormous disproportionate toll on people of color, and the torrent of online misinformation? We urgently need data reflective of today's circumstances along with the policy to ensure it is quickly and effectively disseminated to the public health and clinical workforce.
Last year prompted in part by the measles outbreaks, Reps. Michael C. Burgess (R-TX) and Kim Shrier (D-WA), both physicians, introduced the bipartisan Vaccines Act to develop a national surveillance system to monitor vaccination rates and conduct a national campaign to increase awareness of the importance of vaccines. Unfortunately, that legislation wasn't passed. In response to COVID-19, Senate HELP Committee Ranking member Patty Murray (D-WA) has sought funds to strengthen vaccine confidence and combat misinformation with federally supported communication, research, and outreach efforts. Leading experts outside of Congress have called for this type of research, including the Sabin-Aspen Vaccine Science Policy Institute. Most recently, the National Academy of Sciences, in its report regarding the equitable distribution of the COVID-19 vaccine, included as one of its recommendations the need for "a rapid-response program to advance the science behind vaccine confidence."
Addressing trust in vaccination has never been as challenging nor as consequential. The stunning scientific achievement of COVID-19 vaccines anticipated to be ready in record time needs to be backed up by an equally ambitious and evidence-based effort to build the public's confidence in the vaccines. In its remaining days, the Trump Administration should invest in building vaccine confidence with current resources, targeting efforts to ensure COVID vaccines reduce rather than exacerbate racial and ethnic health disparities. Congress must also act to provide the additional research and outreach resources needed as well as pass the Vaccines Act so we are better prepared in the future.
If we don't succeed, COVID-19 will continue wreaking havoc on our health, our society, and our economy. We will also permanently jeopardize public trust in vaccines – one of the most successful medical interventions in human history.