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William Ludwig was a 64-year-old retired corrections officer living in Bridgeton, New Jersey, in 2010, when he received a near-hopeless cancer prognosis. The Abramson Cancer Center at the University of Pennsylvania had run out of chemotherapeutic options, and Ludwig was disqualified from most clinical trials since he had three cancers at once—leukemia, lymphoma, and squamous cell skin cancer. In a later interview, the scientist Carl June described Ludwig’s condition as “Almost dead.”
Alison Loren, an oncologist at Penn, had been taking care of Ludwig for five painful years. If chemotherapy is not effective early on, each new round brings diminishing returns, and it becomes more and more toxic, she told me. In Ludwig’s case, its toxic side-effects were outdoing any progress scaling back the battalions of cancer cells.
The chemo was suppressing Ludwig’s immune system, since it was his immune system’s B cells, precisely the cells being targeted by the chemo treatments, that were cancerous, expanding uncontrollably in his bone marrow. An infection from an old chicken pox virus broke out in his right eye. And the cancer now appeared to be mobile, or what doctors call “motile,” riddling far-flung sites in his body. Ludwig’s skin cancer looked to Loren as if it had spread, or metastasized, from his bones.
It was about that time when Loren approached Ludwig about a new arrow that doctors at Penn had in their quiver. It was an indigenous strategy, and a radical and dangerous one. “William is the most lovely, humble human being,” Loren said. “I don’t think he realized how groundbreaking this would be at the time. He was almost casual about it. He looked at me, and shrugged, ‘I’ll give it a shot.’”
The hodgepodge of code made it a “Rube Goldberg-like solution” and “truly a zoo.”
In short, the Penn scientists wanted to use engineering tricks to replicate the precision targeting ability of antibodies—Y-shaped proteins that come in billions of varieties—to target a marker on Ludwig’s cancer. Antibodies normally bind to molecular markers called antigens, tagging them to be disposed of by scavenger cells. B-cells and other antigen presenting cells can also lock onto the antigen. Then other immune system cells, such as helper T-cells notice the resulting structure, lock onto it, and unleash a powerful wrath of signaling molecules called cytokines to stir up the immune response. Killer T-cells also carry out lethal attacks on microbes carrying unauthorized antigen badges. T-cells carry a powerful thwack on their own, but they’re less effective without the precision targeting of the antibodies.
Zelig Eshhar, an immunologist at the Weizmann Institute in Israel, came up with a plan to combine them. By 1989 he had invented “chimeric antigen receptor T-cells,” or CAR-Ts, first describing them as “T-bodies.” They were made up of scrambled viruses carrying a brand new human gene. The viruses clandestinely slipped inside human cells, carrying the gene with them. Once in place, the gene would build a new receptor on T-cells that would mimic the targeting function of antibodies, helping them lock onto to cancerous cells. June, Bruce Levine, and colleagues elsewhere, would later improve CAR T-cells by helping them grow in real biological systems.
Scientists could code a homing device into Ludwig’s T-cells and have a small population of these act as a sort of contract security force, added to aid the national security forces of his immune system. It was a gene designed on a computer and then cobbled together into disabled HIV, incorporating bits of genetic code from mice, cows, and woodchucks. If “chimera” signifies a new species, a hybrid that did not exist before in nature, in this case, it was a chimeric molecule of DNA. June noted the hodgepodge of code made it a “Rube Goldberg-like solution” and “truly a zoo.”
Loren explained the procedure to Ludwig in detail. Blood would be drawn from one of his veins and run through a machine that would separate out from it some T-cells. Those cells would then be edited by sending a virus into them that would travel into the cell nucleuses and install a synthetic gene at a random spot in his genome. That engineered gene would code a protein to build a receptor enabling the T-cells to recognize a certain cell surface marker called CD19 on Ludwig’s cancerous B cells, giving them a precision-guidance system. Hopefully, after the doctored cells returned to his blood system, they would go on the attack. With the engineered cells added to the fight, scientists said Ludwig’s faltering immune system might be mobile, responsive, and lethal enough to defeat the cancer. There was a chance that his immune system would go into overdrive, and there was a chance that the edited T-cells wouldn’t be as potent as they expected. The medical team just really couldn’t be sure what would happen. It had never been tried before. So it was that William Ludwig became known, for a time, as Patient Number One.
The nurses didn’t know it then, but his T-cells were killing the cancer.
He was checked into the hospital on July 31, 2010. For a few days after the doctored cells returned to his blood system, nothing spectacular happened. He had a second infusion. But then, 10 days later, before the third and final infusion, chaos broke. Ludwig’s whole body began to shake. His heart rate shot up, his blood pressure collapsed. He got a fever.
“I was put into intensive care. I wasn’t supposed to survive,” Ludwig recalled. The nurses didn’t know it then, but his T-cells were killing the cancer. “A cytokine storm,” Loren told me. “The engineered T-cells were ‘engrafting’ in the body, meeting up with target antigens, and unleashing a whirlwind of cytokines.” Those signaling molecules were firing up the immune system, stirring fevers and opening capillaries so immune cells could rush through the highways of the blood stream to reach the targets. Loren explains, “We now know from watching many patients that a strong immune response means the therapy is working.” The storm that Ludwig was thrown into lasted hours, but was an order of magnitude beyond the intensity that most of us have experienced during our worst case of the flu. And just as quickly as it began, the storm was over.
After almost a month passed, clinicians came into Ludwig’s hospital room on a Tuesday to ask for a bone marrow sample to test for cancer. “It’s not very pleasant, and I’m a tough person to ask for a bone marrow sample,” Ludwig told me. He reluctantly agreed. “Bill doesn’t love them,” Loren said. She pierced his hip bone with a needle and drew a cord of bone marrow about 1 to 2 centimeters long that would demonstrate the composition of cells in circulation in the body. Healthy bone marrow biopsies include a balance of red blood cells, platelets, immune cells, and hodgepodge cells that belong to the “hematopoietic” family of cells. Cancerous marrow is dominated by one cell type, “sheets and sheets” of lymphocytes, Loren said.
Loren peered under the microscope. “It just didn’t seem possible,” she said. There were no sheets of cancer cells in the bone marrow. She had seen the striated layers of sheets under the same microscope just a month ago. Two days later, Ludwig was asked for a second bone marrow sample. No sheets. “I couldn’t believe it. This type of thing doesn’t happen in medicine,” Loren told me. She peeked into Ludwig’s room the next week. “Can you believe it? The staff mixed up the samples and I had to repeat the bone marrow test,” Ludwig complained, grumpily. “Not so,” Loren chided. “The first draw wasn’t a great sample. It was diluted with blood. We really didn’t think the first test was correct,” Loren said. “Honestly. We didn’t know what to say. William, there is no more cancer in your body.”
Months passed. “We kept waiting for the other shoe to drop,” she told me. A year after his treatment, Ludwig asked her a question: “Alison, why don’t you ever say that I’m cured?” Loren explained to him that definitions for a cure are usually based on decades of research, hundreds of patients, mountains of data. “William,” she told him. “You’re the only one.”
Emily Whitehead was the first child treated with a CAR T-cell in 2012, and now has been cancer free for five years.
A small population of mercenary cells appeared to have defeated the cancer. But that cell population might not last forever. I asked Ludwig what will happen when the small troop of cells, the synthetic security forces, finally die out, and leave only the national security forces to defend the body. Would it be a strong enough defense system? Or could the cancer return? “That was the first question we all asked,” he said. “No one knows.”
June estimated his genetically engineered T-cells had wiped out two pounds of Ludwig’s cancer in less than a month. “Drugs don’t do that,” June told a reporter. Soon there was a Patient Number Two, and then, a Patient Number Three. Doctors saw it wipe out a range of 3.5 to 7.7 pounds of cancer in a matter of days among three different patients. Within a few years, hundreds of patients’ saw their bodies cleared of cancers. June’s group at the University of Pennsylvania and colleagues at the Children’s Hospital of Philadelphia were reporting jaw-dropping success in the use of CAR-Ts to treat an acute lymphoblastic leukemia, a childhood cancer. Emily Whitehead, age 7, of Philadelphia, and Avery Walker, 10, of Redmond, Oregon, were splashed all over the pages of major newspapers. “Young cancer patient’s good news: ‘Total remission!’” trumpeted The Philadelphia Inquirer. “In Girl’s Last Hope, Altered Immune Cells Beat Leukemia,” declared The New York Times.
But not all cancer patients responded positively. And no one knew why gene therapy threw some patients, like Ludwig, into violent convulsions and tremors, and why some patients responded only with a slight fever. Whitehead had the same procedure to treat childhood leukemia, and her body reacted so violently to the gene therapy treatment that it almost killed her. But days later, the fever was gone, and so was her cancer. Walker also had the treatment. “We were all waiting for the big storm,” her father Aaron Walker told The Philadelphia Inquirer. But she only got a slight fever. Sadly, Walker and Madison Gorman subsequently relapsed and died.
Many technical challenges lay ahead for scientists genetically engineering T-cells to fight cancer. CAR T-cells were being tweaked so that their receptors had a stronger binding affinity to markers that were more prevalent to cancer cells, so that those cancer cells could be preferentially targeted. In one study, scientists at Penn showed they could develop CAR T-cells with high affinities to cell surface targets that are highly expressed on cancer cells such as breast cancer. But many of these genes also show up in small traces in delicate tissues, like the heart or thymus. In 2013, June and colleagues at Penn reported a major problem: a TCR-Engineered T-cell—an engineered T-cell that binds to cancer antigens concealed inside the cancer cell—designed to attach to MAGE-A3 in cancer cells, also began to attach to the product of the gene TTN, which builds Titin, the largest protein in the human body. This “off target effect” led to cardiac events in some patients.
Since then, researchers at Penn went back to the drawing board to work on affinity tuning, devising CAR T-cells that form weaker bonds to targets. A Journal of Clinical Oncology paper suggested that doctors had the ability to use biomarkers to predict which patients might experience adverse events from such an infusion of CAR T-cells. But, accidents with engineered T-cells continue to be reported. In March, Juno slammed to a halt one of its clinical trials for CAR T-cells designed to attach to CD19 on the surface of cancerous white blood cells after 5 of 38 patients injected with the engineered T-cells died in the trial, due to a mysterious inflammatory reaction in the brain. In May, Kite Pharma reported a death with a similar product due to a similar adverse event.
Nevertheless, Novartis, a Swiss multinational biotech giant, appears on the verge of commercializing the treatment. On Wednesday, an FDA panel recommended approval of the first CAR T-cell, for childhood leukemia, which is expected to sell commercially at $300,000. Emily Whitehead was the first child treated with a CAR T-cell in 2012, and now has been cancer free for five years. Whitehead was treated just months after the first adult, Patient Number One, was treated—William Ludwig.
I telephoned him on a lark on a Sunday afternoon in 2013, three years after his treatment. He had just returned from an RV trip to New York City with his wife and two grandkids, and was bound for the Adirondacks. I assumed he was doing fine, but was he? “I’m no spring chicken,” he said, “but I think I’m doing well for someone my age.” He had an atypical skin growth, a chronic cough, a sinus infection, a puddle of fluid at the bottom of his lungs, a virus in his right eye, and bad heartburn. But he didn’t have cancer.
“Being Patient Number One is overwhelming to think about sometimes,” Ludwig said. “I knew my days were numbered. I had nothing to lose.” His wife stuck with him for more than a decade as he fought it, “a spectacular person,” he told me. Not more than a week later, Ludwig and his wife were driving the RV to Cooperstown with another couple to watch children play baseball. The verdant summer was upon them, the windows rolled down, the couples in their shirt sleeves, coasting on the old highways of upstate New York, clear and starlit.
Jim Kozubek is a data scientist living in Cambridge, Massachusetts, and the author of Modern Prometheus: Editing the Human Genome with Crispr-Cas9.
This story was partially excerpted from Modern Prometheus: Editing the Human Genome with CRISPR-Cas9, by Jim Kozubek, and was originally published on Cancer Focus in July 2017.
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