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.
The U.S. must fund more biotech innovation – or other countries will catch up faster than you think
The U.S. has approximately 58 percent of the market share in the biotech sector, followed by China with 11 percent. However, this market share is the result of several years of previous research and development (R&D) – it is a present picture of what happened in the past. In the future, this market share will decline unless the federal government makes investments to improve the quality and quantity of U.S. research in biotech.
The effectiveness of current R&D can be evaluated in a variety of ways such as monies invested and the number of patents filed. According to the UNESCO Institute for Statistics, the U.S. spends approximately 2.7 percent of GDP on R&D ($476,459.0M), whereas China spends 2 percent ($346,266.3M). However, investment levels do not necessarily translate into goods that end up contributing to innovation.
Patents are a better indication of innovation. The biotech industry relies on patents to protect their investments, making patenting a key tool in the process of translating scientific discoveries that can ultimately benefit patients. In 2020, China filed 1,497,159 patents, a 6.9 percent increase in growth rate. In contrast, the U.S. filed 597,172, a 3.9 percent decline. When it comes to patents filed, China has approximately 45 percent of the world share compared to 18 percent for the U.S.
So how did we get here? The nature of science in academia allows scientists to specialize by dedicating several years to advance discovery research and develop new inventions that can then be licensed by biotech companies. This makes academic science critical to innovation in the U.S. and abroad.
Academic scientists rely on government and foundation grants to pay for R&D, which includes salaries for faculty, investigators and trainees, as well as monies for infrastructure, support personnel and research supplies. Of particular interest to academic scientists to cover these costs is government support such as Research Project Grants, also known as R01 grants, the oldest grant mechanism from the National Institutes of Health. Unfortunately, this funding mechanism is extremely competitive, as applications have a success rate of only about 20 percent. To maximize the chances of getting funded, investigators tend to limit the innovation of their applications, since a project that seems overambitious is discouraged by grant reviewers.
Considering the difficulty in obtaining funding, the limited number of opportunities for scientists to become independent investigators capable of leading their own scientific projects, and the salaries available to pay for scientists with a doctoral degree, it is not surprising that the U.S. is progressively losing its workforce for innovation.
This approach affects the future success of the R&D enterprise in the U.S. Pursuing less innovative work tends to produce scientific results that are more obvious than groundbreaking, and when a discovery is obvious, it cannot be patented, resulting in fewer inventions that go on to benefit patients. Even though there are governmental funding options available for scientists in academia focused on more groundbreaking and translational projects, those options are less coveted by academic scientists who are trying to obtain tenure and long-term funding to cover salaries and other associated laboratory expenses. Therefore, since only a small percent of projects gets funded, the likelihood of scientists interested in pursuing academic science or even research in general keeps declining over time.
Efforts to raise the number of individuals who pursue a scientific education are paying off. However, the number of job openings for those trainees to carry out independent scientific research once they graduate has proved harder to increase. These limitations are not just in the number of faculty openings to pursue academic science, which are in part related to grant funding, but also the low salary available to pay those scientists after they obtain their doctoral degree, which ranges from $53,000 to $65,000, depending on years of experience.
Thus, considering the difficulty in obtaining funding, the limited number of opportunities for scientists to become independent investigators capable of leading their own scientific projects, and the salaries available to pay for scientists with a doctoral degree, it is not surprising that the U.S. is progressively losing its workforce for innovation, which results in fewer patents filed.
Perhaps instead of encouraging scientists to propose less innovative projects in order to increase their chances of getting grants, the U.S. government should give serious consideration to funding investigators for their potential for success -- or the success they have already achieved in contributing to the advancement of science. Such a funding approach should be tiered depending on career stage or years of experience, considering that 42 years old is the median age at which the first R01 is obtained. This suggests that after finishing their training, scientists spend 10 years before they establish themselves as independent academic investigators capable of having the appropriate funds to train the next generation of scientists who will help the U.S. maintain or even expand its market share in the biotech industry for years to come. Patenting should be given more weight as part of the academic endeavor for promotion purposes, or governmental investment in research funding should be increased to support more than just 20 percent of projects.
Remaining at the forefront of biotech innovation will give us the opportunity to not just generate more jobs, but it will also allow us to attract the brightest scientists from all over the world. This talented workforce will go on to train future U.S. scientists and will improve our standard of living by giving us the opportunity to produce the next generation of therapies intended to improve human health.
This problem cannot rely on just one solution, but what is certain is that unless there are more creative changes in funding approaches for scientists in academia, eventually we may be saying “remember when the U.S. was at the forefront of biotech innovation?”
New gene therapy helps patients with rare disease. One mother wouldn't have it any other way.
Three years ago, Jordan Janz of Consort, Alberta, knew his gene therapy treatment for cystinosis was working when his hair started to darken. Pigmentation or melanin production is just one part of the body damaged by cystinosis.
“When you have cystinosis, you’re either a redhead or a blonde, and you are very pale,” attests Janz, 23, who was diagnosed with the disease just eight months after he was born. “After I got my new stem cells, my hair came back dark, dirty blonde, then it lightened a little bit, but before it was white blonde, almost bleach blonde.”
According to Cystinosis United, about 500 to 600 people have the rare genetic disease in the U.S.; an estimated 20 new cases are diagnosed each year.
Located in Cambridge, Mass., AVROBIO is a gene therapy company that targets cystinosis and other lysosomal storage disorders, in which toxic materials build up in the cells. Janz is one of five patients in AVROBIO’s ongoing Phase 1/2 clinical trial of a gene therapy for cystinosis called AVR-RD-04.
Recently, AVROBIO compiled positive clinical data from this first and only gene therapy trial for the disease. The data show the potential of the therapy to genetically modify the patients’ own hematopoietic stem cells—a certain type of cell that’s capable of developing into all different types of blood cells—to express the functional protein they are deficient in. It stabilizes or reduces the impact of cystinosis on multiple tissues with a single dose.
Medical researchers have found that more than 80 different mutations to a gene called CTNS are responsible for causing cystinosis. The most common mutation results in a deficiency of the protein cystinosin. That protein functions as a transporter that regulates a lot metabolic processes in the cells.
“One of the first things we see in patients clinically is an accumulation of a particular amino acid called cystine, which grows toxic cystine crystals in the cells that cause serious complications,” explains Essra Rihda, chief medical officer for AVROBIO. “That happens in the cells across the tissues and organs of the body, so the disease affects many parts of the body.”
Jordan Janz, 23, meets Stephanie Cherqui, the principal investigator of his gene therapy trial, before the trial started in 2019.
Jordan Janz
According to Rihda, although cystinosis can occur in kids and adults, the most severe form of the disease affects infants and makes up about 95 percent of overall cases. Children typically appear healthy at birth, but around six to 18 months, they start to present for medical attention with failure to thrive.
Additionally, infants with cystinosis often urinate frequently, a sign of polyuria, and they are thirsty all the time, since the disease usually starts in the kidneys. Many develop chronic kidney disease that ultimately progresses to the point where the kidney no longer supports the body’s needs. At that stage, dialysis is required and then a transplant. From there the disease spreads to many other organs, including the eyes, muscles, heart, nervous system, etc.
“The gene for cystinosis is expressed in every single tissue we have, and the accumulation of this toxic buildup alters all of the organs of the patient, so little by little all of the organs start to fail,” says Stephanie Cherqui, principal investigator of Cherqui Lab, which is part of UC San Diego’s Department of Pediatrics.
Since the 1950s, a drug called cysteamine showed some therapeutic effect on cystinosis. It was approved by the FDA in 1994 to prevent damage that may be caused by the buildup of cystine crystals in organs. Prior to FDA approval, Cherqui says, children were dying of the disease before they were ten-years-old or after a kidney transplant. By taking oral cysteamine, they can live from 20 to 50 years longer. But it’s a challenging drug because it has to be taken every 6 or 12 hours, and there are serious gastric side effects such as nausea and diarrhea.
“With all of the complications they develop, the typical patient takes 40 to 60 pills a day around the clock,” Cherqui says. “They literally have a suitcase of medications they have to carry everywhere, and all of those medications don’t stop the progression of the disease, and they still die from it.”
Cherqui has been a proponent of gene therapy to treat children’s disorders since studying cystinosis while earning her doctorate in 2002. Today, her lab focuses on developing stem cell and gene therapy strategies for degenerative, hereditary disorders such as cystinosis that affect multiple systems of the body. “Because cystinosis expresses in every tissue in the body, I decided to use the blood-forming stem cells that we have in our bone marrow,” she explains. “These cells can migrate to anywhere in the body where the person has an injury from the disease.”
AVROBIO’s hematopoietic stem cell gene therapy approach collects stem cells from the patient’s bone marrow. They then genetically modify the stem cells to give the patient a copy of the healthy CTNS gene, which the person either doesn’t have or it’s defective.
The patient first undergoes apheresis, a medical procedure in which their blood is passed through an apparatus that separates out the diseased stem cells, and a process called conditioning is used to help eliminate the damaged cells so they can be replaced by the infusion of the patient’s genetically modified stem cells. Once they become engrafted into the patient’s bone marrow, they reproduce into a lot of daughter cells, and all of those daughter cells contain the CTNS gene. Those cells are able to express the healthy, functional, active protein throughout the body to correct the metabolic problem caused by cystinosis.
“What we’re seeing in the adult patients who have been dosed to date is the consistent and sustained engraftment of our genetically modified cells, 17 to 27 months post-gene therapy, so that’s very encouraging and positive,” says Rihda, the chief medical officer at AVROBIO.
When Janz was 11-years-old, his mother got him enrolled in the trial of a new form of cysteamine that would only need to be taken every 12 hours instead of every six. Two years later, she made sure he was the first person on the list for Cherqui’s current stem cell gene therapy trial.
AVROBIO researchers have also confirmed stabilization or improvement in motor coordination and visual perception in the trial participants, suggesting a potential impact on the neuropathology of the disease. Data from five dosed patients show strong safety and tolerability as well as reduced accumulation of cystine crystals in cells across multiple tissues in the first three patients. None of the five patients need to take oral cysteamine.
Janz’s mother, Barb Kulyk, whom he credits with always making him take his medications and keeping him hydrated, had been following Cherqui’s research since his early childhood. When Janz was 11-years-old, she got him enrolled in the trial of a new form of cysteamine that would only need to be taken every 12 hours instead of every six. When he was 17, the FDA approved that drug. Two years later, his mother made sure he was the first person on the list for Cherqui’s current stem cell gene therapy trial. He received his new stem cells on October 7th, 2019, went home in January 2020, and returned to working full time in February.
Jordan Janz, pictured here with his girlfriend, has a new lease on life, plus a new hair color.
Jordan Janz
He notes that his energy level is significantly better, and his mother has noticed much improvement in him and his daily functioning: He rarely vomits or gets nauseous in the morning, and he has more color in his face as well as his hair. Although he could finish his participation at any time, he recently decided to continue in the clinical trial.
Before the trial, Janz was taking 56 pills daily. He is completely off all of those medications and only takes pills to keep his kidneys working. Because of the damage caused by cystinosis over the course of his life, he’s down to about 20 percent kidney function and will eventually need a transplant.
“Some day, though, thanks to Dr. Cherqui’s team and AVROBIO’s work, when I get a new kidney, cystinosis won’t destroy it,” he concludes.