, New Jersey, when he received an almost hopeless forecast due to cancer. The Abramson Cancer Center at the University of Pennsylvania had chemotherapy options ended, and Ludwig was expelled from almost all clinical trials because he had three types of cancer at once: leukemia, lymphoma and squamous cell carcinoma (skin cancer). In this later interview, scientists Karl June described Ludwig's condition as "practically dead."
Alison Lauren [Alison Loren]an oncologist from Pennsylvania, took care of Ludwig for five agonizing years. If chemotherapy is immediately ineffective, then every new cycle produces less and less results, and, she says, it is becoming increasingly toxic. In the case of Ludwig, toxic side effects nullified any progress in the fight against cancer cells.
Chemotherapy suppressed Ludwig's immune system, as B-lymphocytes, immune system cells, were precisely those cells to which chemotherapy was targeted. They were affected by cancer, which spread uncontrollably in the bone marrow. In his right eye, an infection from the old chickenpox virus was played out. Cancer has become mobile, or, as doctors say, "mobile", reaching to the farthest places in his body. Lauren believed that Ludwig's skin cancer looked as if it had spread through metastases from his bones.
Around that time, Lauren offered Ludwig a new trick, which appeared on the list of doctors of the institute. The strategy was local, radical and very dangerous. "William is a fine, humble man," Lauren says. "I do not think he understood how revolutionary this was at that time." He treated this as self-evident. He looked at me and shrugged his shoulders: "I'll try."
In short, university scientists wanted to use engineering tricks to recreate the possibility of an accurate sight, present in antibodies – Y-shaped proteins, which have millions of options – to Aim at the Ludwig cancer marker. Antibodies usually attach to molecular marker antigens, noting that they must be disposed of by cleansing cells. B cells and other cells with antigens are able to target the antigen. Then other cells of the immune system, T-helpers, notice the final structure, attach to it and give out a violent stream of signaling molecules, cytokines, to arouse the immune response. T-killers also organize deadly attacks on microbes that carry unauthorized antigens. T cells are capable of attacking themselves, but they are not so effective without precise targeting of antibodies.
Zelig Eshar [Zelig Eshhar]an immunologist from Weizmann Institute in Israel, came up with how to combine these approaches. By 1989, he invented the "chimeric receptor for T cell antigens", CAR-T, describing them as "T-bodies." They were created from mixed viruses that carry the new human gene. Viruses secretly penetrated into human cells, transferring this gene. In situ, the gene created a new receptor on T cells, simulating the function of targeting antibodies, helping them to target the cancer cells. June, Bruce Levin and their colleagues later improved CAR T-cells, helping to grow them in real biological systems.
Scientists could encode a self-guided device in Ludwig T-cells, and use a small number of them as kind of mercenaries fighting On the side of the national guard of his immune system. This gene was developed on the computer and then confused with the neutralized HIV, adding the genetic code obtained from mice, cows and marmots. If the "chimera" denotes a new species, a hybrid that did not exist in nature, then in this case it was a chimeric DNA molecule. June noted that this mishmash of code resembled the creations of Rub Goldberg, and was "a real zoo."
Lauren described Ludwig in detail the procedure. From his vein will take the blood, run through the machine, which will separate several of its T-cells. These cells are edited by sending to them a virus that will get into their nuclei and install a synthetic gene there at the random place of its genome. This developed gene encodes a protein to construct a receptor that allows T cells to recognize a specific cell surface marker, called CD19, in Ludwig cancer cells, which will give them an accurate targeting system. With a successful combination of circumstances, after the edited cells return to the circulatory system, they will engage in an attack. And with the help of these cells, Ludwig's immune system can become mobile, responsive and strong enough to defeat cancer. There was a chance that she would show feverish activity, or that the edited T-cells would not be as powerful as they were expected. The medical team simply could not be sure of the result. No one has ever tried it. So at that moment, William Ludwig became known as the number one patient.
He was put in a hospital on July 31, 2010. A few days after the edited cells returned to his circulatory system, nothing interesting happened. He was introduced to another party. But then, ten days later, until the third, last injection, chaos erupted. Ludwig's body began to shake. His pulse took off, the pressure fell. He began to fever.
"They put me in intensive care. I should not have survived, "Ludwig recalls. Then the nurses did not know this, but his T-cells began to kill the cancer. "A cytokine storm," Lauren told me. "The edited T cells" inoculated "in his body, met the target antigens, and attacked with cytokine fluxes." These signaling molecules worked in the immune system, causing fever and opening the capillaries so that the immune cells could rush through the vessels and reach the targets. Lauren explains: "Now, after observing a lot of patients, we know that a strong immune response means that the therapy has worked." Ludwig's storm lasted for hours, but it was much weaker than most of us feel when there is a strong flu. As quickly as it began, the storm stopped.
Almost a month later the doctors came to Ludwig's room on Tuesday to take a bone marrow test for examination. "It's not very pleasant, and I'm not the kind of person who can easily be asked to take a bone marrow test," Ludwig told me. Reluctantly, he agreed. "Bill does not like them," Lauren says. She pierced his thigh bone with a needle and took a bone marrow sample 1-2 cm long, which will show the composition of cells circulating in the body. A healthy bone marrow biopsy shows a balance between red blood cells, platelets, immune cells and a mixture of hematopoietic cells. In a cancer-affected brain, one type of cell predominates, lymphocytes.
Lauren looked through the microscope. "It seemed incredible," she says. There were no cancer cells in the bone marrow. She saw striped stripes of cells through the same microscope a month ago. Two days later, another sample was taken from Ludwig. No strips. "I could not believe it. This is not the case in medicine, "Lauren told me. She looked into the room to Ludwig next week. "You will not believe – the staff confused the samples, and I had to repeat the test for the bone marrow, – grumbling, complained to her Ludwig. "No, it is not," replied Lauren. – The first sample was bad, it was contaminated with blood. We did not think that the first test was the right one, "she said. – Honestly, we do not know what to say. William, there is no cancer in your body anymore. "
Months passed. "We've all been waiting for a dirty trick," she told me. A year after the treatment, Ludwig asked her: "Alison, why do not you tell me that I'm cured?" Lauren explained to him that the definitions of treatment are based on decades of research, hundreds of patients, mountains of data. "William," she told him, "you are the only one."
A small squad of mercenary cells has won cancer. But this population of cells may not survive. I asked Ludwig what would happen when a small set of cells, synthetic guards, would die, and only the forces of the national guard would remain on the body. Will this be a strong enough security system? Or can the cancer come back? "This was the first question that everyone asked," he said. "No one knows."
June believes that his artificially created T cells have eliminated kilograms of Ludwig cancer cells in less than a month. "Medicines are not capable of this," said June to the reporter. Soon there was a patient number two, then patient number three. Doctors watched the destruction of 2 to 4 kilograms of cancer for several days in three different patients. For several years, hundreds of patients have observed the purification of their bodies from cancer. June's group from the University of Pennsylvania and colleagues from the Children's Hospital in Philadelphia reported incredible success in using CAR-T to treat acute lymphoblastic leukemia and childhood cancer. Emily Whitehead, 7, from Philadelphia, and Avery Walker, 10, from Redmond, Oregon, appeared on the pages of the central newspapers. "Good news for a young patient with cancer: complete remission!" – the newspaper The Philadelphia Inquirer proclaimed. "The girl's last hope, the edited cells of the immune system, defeated leukemia," declared The New York Times.
But not all patients responded positively. Nobody knew why gene therapy causes such severe convulsions and tremors in some patients as in Ludwig, and in others – a small fever. Whitehead underwent the same procedure in treating childhood leukemia, and her body reacted so strongly that she nearly died. But a few days later the fever was gone, like cancer. Walker was also treated. "We've all been waiting for a big storm," her father Aaron Walker told The Philadelphia Inquirer. But she had only a small fever. Unfortunately, Walker and Madison Gorman later had a relapse, and they died.
There are many technical barriers to scientists editing T-cells to fight cancer. CAR T-cells were adjusted so that their receptors were more similar to markers, more common in cancer cells, to preferentially target these cells. In one study, scientists at the University of Pennsylvania showed that they were able to develop T cells that are very close to those that are well expressed in cancer cells such as breast cancer. But many of these genes are found in small quantities in such delicate tissues as the heart or thymus. In 2013, June and colleagues reported an important problem: T cells created through TCR, tied to cancer antigens concealed inside a cancer cell, designed to connect with MAGE-A3 in cancer cells, began to bind to the products of the TTN gene that create titin, The largest of the human proteins. In some patients, this caused heart problems.
Since then, researchers have returned back to the drawing board to work on adjustments and changes in T cells that form weaker bonds with target cells. The paper, published in the Journal of Clinical Oncology, suggests that physicians have the opportunity to use biomarkers to predict which patients may develop hostile responses to the introduction of CAR T cells. But incidents with edited T-cells are still happening. In March, June stopped clinical trials of T cells designed to connect to CD19 on the surface of white-body cancer cells, after 5 of 38 patients died on tests due to a mysterious inflammatory reaction in the brain. In May, Kite Pharma, a cancer control company, reported similar deaths.
Nevertheless, Novartis, the international Swiss biotechnology giant, is on the verge of commercializing treatment. In July 2017, the US Food and Drug Administration recommended the approval of the first CAR T-cells for pediatric leukemia, which will be sold at a price of $ 300,000. Emily Whitehead was the first child treated with such cells in 2012, And now she has not had cancer for five years. She was treated only a few months after the patient number one, William Ludwig.
I called him in 2013, three years after the treatment. He had just returned from an autotravel trip to New York with his wife and two grandchildren, and was about to leave for the Adirondack Mountains. I assumed that he was all right – but was it really so? "Of course, I'm no longer a young man," he said, "but it seems to me that I am being normal for my age." He had atypical skin growth, chronic cough, infection of nasal sinuses, fluid in the lungs, a virus in the right eye and severe heartburn. But there was no cancer.
"Sometimes I get overwhelmed by the thought that I am the number one patient," Ludwig said. "I knew that my days were numbered." I had nothing to lose. " His wife was with him for over a decade, while he struggled with the disease – "an amazing person," he said. Less than a week after the conversation, Ludwig and his wife went to their Cooperstown motorhomes with another couple to see how the children play baseball. It was green summer, the windows were open, pairs of short sleeved T-shirts rolled along the old highway of New York State, clean and flooded with stars.
Jim Kozubek is a data processing specialist who lives in Cambridge, Massachusetts. The author of the book "Modern Prometheus: editing the genome of a man with the technology of Crispr-Cas9."