A person who received an update of the immune system to fight cancer

William Ludwig was a 64-year-old retired prison warden in 2010 and lived in Bridgton, New Jersey when he received an almost hopeless prediction due to cancer. The Abramson Cancer Center at the University of Pennsylvania ended up with chemotherapy options, and Ludwig was excluded from almost all clinical trials, since he had three types of cancer at once - leukemia, lymphoma and squamous cell carcinoma (skin cancer). In this later interview, scientists Carl June described the state of Ludwig as "almost dead."



Alison Loren, an oncologist from Pennsylvania, took care of Ludwig for five agonizing years. If chemotherapy is immediately ineffective, then each new cycle produces fewer results, and, according to her, it becomes more and more toxic. In the case of Ludwig, the toxic side effects negated any progress in the fight against cancer cells.



Chemotherapy suppressed the immune system of Ludwig, since the B-lymphocytes , cells of the immune system, were the cells that chemotherapy was aimed at. They were struck by cancer that was spreading out of control in the bone marrow. An infection from an old chickenpox virus broke out in his right eye. Cancer became mobile, or, as doctors say, "mobile", reaching the most distant places in his body. Loren believed that Ludwig’s skin cancer looked like it had spread through metastases from its bones.



At about that time Lauren offered Ludwig a new trick, which appeared in the recruitment of the doctors of the institute. The strategy was local, radical and very dangerous. “William is a wonderful, modest person,” says Lauren. “I don’t think he understood how revolutionary this was at that time.” He took it as a matter of course. He looked at me and shrugged: "I'll try."



In short, university scientists wanted to use engineering tricks to recreate the exact scope that is present in antibodies — Y-shaped proteins, of which there are millions — to target the Ludwig cancer marker. Antibodies usually bind to molecular markers-antigens, noting that they must be disposed of using cleansing cells. B cells and other cells with antigens are able to target antigen. Then other cells of the immune system, T-helper cells , notice the final structure, bind to it and give out a violent flow of signaling molecules, cytokines , to stimulate an immune response. T-killers also organize deadly attacks on microbes that carry illicit antigens. T cells themselves are capable of striking, but they are not as effective without precise targeting of antibodies.



Zelig Eshhar [Zelig Eshhar], an immunologist at the Weizman Institute in Israel, figured out how to combine these approaches. By 1989, he invented the “chimeric T-cell antigen receptor,” 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, carrying this gene. In place of the gene, a new receptor was created on T cells, imitating the function of targeting antibodies, helping them to target cancer cells. June, Bruce Levine, 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's T-cells, and use a small number of them as peculiar mercenaries fighting on the side of the national guard of his immune system. This gene was developed on a computer and then confused with the neutralized HIV, adding the genetic code obtained from mice, cows and marmots. If “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 the code resembled the creation of Rube Goldberg, and was a “real zoo”.



Loren described Ludwig in detail. They will take blood from his veins, drive him through a machine that will separate several of his T-cells. These cells will be edited by sending the virus to them, which will sneak into their nuclei and install a synthetic gene there in a random place of its genome. This gene developed encodes a protein for the construction of a receptor that allows T cells to recognize a certain cell surface marker, called CD19, in Ludwig’s cancer B cells, which will give them an accurate guidance system. With a successful set of circumstances, after the edited cells return to the circulatory system, they will take up the 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 to be. The medical team simply could not be sure of the result. No one has ever tried this. So at that moment, William Ludwig became known as patient number one.



He was taken to hospital on July 31, 2010. A few days after the edited cells returned to his circulatory system, nothing interesting happened. He was given another batch. But then, ten days later, before the third, last injection, chaos broke out. Ludwig's body began to shake. His pulse soared, the pressure dropped. He began to fever.



“They put me in intensive care. I should not have survived, ”recalls Ludwig. Then the nurses did not know it, but his T-cells began to kill the cancer. “Cytokine storm,” Lauren told me. “The edited T cells“ inoculated ”in his body, met with target antigens, and attacked with cytokine flows.” These signaling molecules have been triggered in the immune system, causing fever and opening capillaries so that immune cells can rush through the vessels and reach their goals. Lauren explains: “Now, after seeing many patients, we know that a strong immune response means that the therapy has worked.” Ludwig's storm lasted for hours, but at the same time it was much weaker than most of us feel with strong flu. As quickly as it began, the storm stopped.



Almost a month later, doctors came to the Ludwig ward on Tuesday to take a bone marrow sample for testing. “This is not very pleasant, and I am not the person who can easily be asked to take a bone marrow sample,” Ludwig told me. Reluctantly he agreed. “Bill doesn't love them,” says Lauren. She pierced his femur 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 reveals a balance between red blood cells, platelets, immune cells and a mixture of hematopoietic cells. In the affected brain, one cell type, lymphocytes, predominates.



Lauren looked through a microscope. “It seemed incredible,” she says. There were no cancer cells in the bone marrow. She saw the striped layers of cells through the same microscope a month ago. Two days later, another test was taken from Ludwig. No stripes. “I could not believe it. There is no such thing in medicine, ”Lauren told me. She looked into the room to Ludwig next week. “You won't believe it - the staff confused the samples, and I had to repeat the bone marrow test,” grumbled Ludwig, complaining to her. - No, not so - answered Lauren. - The first test was bad, it was contaminated with blood. “We did not think the first test was correct,” she said. - Honestly, we do not know what to say. William, there's no more cancer in your body. ”



The months went by. “We were all waiting for a trick,” she told me. A year after the treatment, Ludwig asked her: “Alison, why don't you tell me that I recovered?” 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 defeated cancer. But this population of cells may not survive. I asked Ludwig what would happen when a small set of cells, synthetic guards, died, and only the forces of the National Guard would remain to protect the body. Will it be a strong enough protection system? Or can cancer come back? “That was the first question everyone asked,” he said. - Nobody knows".



June believes that his artificially created T-cells eliminated a kilogram of Ludwig cancer cells in less than a month. “Medicines can't do this,” Joon told the reporter. Soon patient number two arrived, then patient number three. Doctors observed killing from 2 to 4 kilograms of cancer over several days in three different patients. For several years, hundreds of patients have watched for the purification of their bodies from cancer. June's group from the University of Pennsylvania and her colleagues from the Children's Hospital in Philadelphia reported incredible success in using CAR-T to treat acute lymphoblastic leukemia, childhood cancer. Emily Whitehead, 7, from Philadelphia, and Avery Walker, 10, from Redmond, Oregon, appeared on the pages of national newspapers. “Good news for a young patient with cancer: a complete remission!” Proclaimed The Philadelphia Inquirer. "The girl's last hope, the edited cells of the immune system, defeated leukemia," announced The New York Times.



But not all patients had a positive response. No one knew why gene therapy in some patients causes such severe convulsions and tremors as in Ludwig, and in others a slight fever. Whitehead underwent the same procedure for treating childhood leukemia, and her body reacted so strongly that she almost died. But a few days later, the fever was gone, as was the cancer. Walker was also treated. “We were all waiting for a big storm,” said her father Aaron Walker to The Philadelphia Inquirer. But she had only a small fever. Unfortunately, Walker and Madison Gorman later relapsed, and they died.



Scientists editing T-cells to fight cancer have many technical barriers. CAR T cells were adjusted so that their receptors were more like markers that are more common in cancer cells, in order to preferentially target these cells. In one study, scientists from the University of Pennsylvania showed that they were able to develop T-cells that are very close to goals, 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 TCRs that bind to cancer antigens hidden inside a cancer cell, designed to connect to MAGE-A3 in cancer cells, also began to connect with the TTN gene products that create titin , the largest of human proteins. In some patients, it caused heart problems.



Since then, researchers have returned to the drawing board to work on adjustments and changes to the T cells that form weaker links with the target cells. The paper , published in the Journal of Clinical Oncology, suggests that physicians have the ability to use biomarkers to predict which patients may have a hostile reaction to the introduction of CAR T cells. But incidents with edited T-cells still happen. In March, June stopped a clinical trial of T-cells designed to connect with CD19 on the surface of white-cell cancer cells, after 5 out of 38 patients died on trials due to a mysterious inflammatory response in the brain. In May, the anti-cancer company Kite Pharma reported a similar death.



However, Novartis, the international Swiss biotech giant, is on the verge of commercializing treatment. In July 2017, the US Food and Drug Administration (FDA) recommended approving the first CAR T-cells for childhood leukemia, which will be priced at $ 300,000. Emily Whitehead was the first child treated with such cells in 2012, and now she has no cancer for five years. She was treated just a few months after patient number one, William Ludwig.



I called him in 2013, three years after the treatment. He had just returned from a road trip to New York with his wife and two grandchildren, and was about to go to the Adirondack Mountains . I assumed that he was all right - but was it really so? “I, of course, is no longer a youth,” he said, “but it seems to me that for my age I am doing fine.” He had atypical skin growth, chronic cough, an infection of the nasal sinuses, fluid in the lungs, a virus in his right eye, and severe heartburn. But there was no cancer.



“Sometimes I am overwhelmed with the thought that I am patient number one,” said Ludwig. - I knew my days were numbered. I had nothing to lose. ” His wife was with him for more than ten years, while he was fighting with the disease - “an amazing man,” he said. Less than a week after the conversation, Ludwig and his wife drove their motorhomes to Cooperstown with another couple to watch the kids play baseball. Green summer was coming, the windows were open, couples in short-sleeved T-shirts rolled along the old New York state highway, clean and bathed in starlight.



Jim Kozubek, a data processing specialist, lives in Cambridge, Massachusetts. Author of the book " Modern Prometheus: editing the human genome with technology Crispr-Cas9 ".