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A T cell hunts and eliminates cancer cells. (Gillian Griffiths / Jonny Settle)
A Promising New Class of Cancer Treatments Recruits Cells Into Our Blood to Fight Tumors, Using Powerful Gene Editing Tools to Transform a Type of White Blood Cell – Called Cell T – an immune cells that normally target bacterial or fungal infections in a live anti-cancer drug.
Genetic alterations may stimulate immune systems to effectively fight cancer on their own. Researchers remove T cells from patients and slide new genes into cells. After clinicians have returned the modified T cells to patients, the cells, like the microscopic bloodhounds, drive the immune system to look for tumors.
"We are living an incredible moment in cancer immunotherapies," says Alexander Marson, Professor of Microbiology and Immunology at the University of California at San Francisco
In 2017, the Food and Drug Administration has begun approving genetically modified immune cells for small groups of patients, such as those with aggressive non-Hodgkin's lymphoma or a rare form of childhood leukemia. Other experimental trials, involving cancers such as myeloma and melanoma, show encouraging results.
But other developments have been slowed down, with a bottleneck not related to bureaucracy but to demand. Liberation systems capable of inserting new genes into immune cells are rare.
Inactive viruses, which inject genes into cells such as a needle prick, are the current norm. Only a few biotechnology companies, equipped with expensive manufacturing systems, can produce the viral vectors. Waiting times for new viruses can reach several years, as stated by James M. Wilson, who runs the gene therapy program at the Perelman School of Medicine at the University of Pennsylvania, at the New York Times in November
. have developed a new, faster method for reprogramming T cells, as they described Wednesday in the journal Nature. Rather than relying on viruses to deliver the genetic package, the researchers shook the T cells with electricity. The shock relaxed the membranes surrounding the cells, making them receptive to new genetic material.
If edited gene chains were floating nearby, as they did in the study, the DNA went through the membrane. With the help of CRISPR-Cas9 – a molecular system often compared to cut-and-paste – the new fused DNA in the nucleus of the cell. "It's a turning point," said Vincenzo Cerundolo, director of the Human Immunology Unit at Oxford University, who did not participate in this event. study. "It's a game changer on the court and I'm sure this technology has legs." He predicts cheaper therapies and much faster development times – as fast as a week, rather than the months needed to make a virus. Researchers previously used the delivery technique, called electroporation, to coax the genetic material into cells. Last year, for example, scientists at Harvard University translated a galloping horse movie into DNA. By electroporation, they inserted the clip (an animated GIF) into bacteria.
In the new research, Theodore Roth, a PhD student in Marson's lab, performed thousands of experiments in quick succession to identify the best way to zap new genes. T. Cells
The effectiveness of the method varies depending on the donor cells and the targeted genes. In healthy volunteer cells, the most successful group, the new genes integrated with up to 35 or 40% of cells.
Roth pointed out that electroporation also allowed researchers to insert genes on "a specific site in the genome". The genes delivered by the jab of a virus are found in a more or less random place, he says.
The authors of the study tested the method in two scenarios. First, they used CRISPR-Cas9 to fix a single mutation in T cells.
Three children in a family have a rare autoimmune disease that prevents the normal functioning of regulatory T cells that keep the immune system online. The researchers took mature immune cells from affected siblings. In a dish, scientists have carefully removed the harmful mutation. They grew hundreds of millions of repaired cells. "By fixing a gene, you can essentially repair" broken cells, said Fred Ramsdell, vice president of research at the Parker Institute for Cancer Immunotherapy in San Francisco. Ramsdell, who was not a member of the team behind the study, called the ability to rapidly rearrange T cells xtraordinarily significant . "
A bone marrow transplant, the existing treatment for similar autoimmune diseases, forces patients to take immunosuppressive drugs for life. For this reason, said co-author of the study Kevan Herold, an endocrinologist and immunologist at Yale University, the family was eager to find other options. Herold and his colleagues are seeking FDA approval to treat the family with repaired T cells.
"There will be discussions with regulators," Herold said. "We are all aware of the potential pitfalls here." Researchers must answer a "first critical question: are these cells safe to be handed to people?"
In the second scenario, also completed in vitro , researchers reworked T cells at home on melanoma cells. Electroporation has opened the doors for large amounts of genetic material to enter the cell. The authors stated that previous nonviral insertions had been limited to short segments of no more than a dozen bases – the letters that make up the code of DNA. The new technique has inserted hundreds of bases
Such a long chain has enabled scientists, essentially, to renovate a specific part of the T cell.
T cells have small protruding receptors, such as probes, which identify invaders. Cancers such as melanoma can escape the detectors. The authors of the study replaced the T-cell receptor with probes that detect melanoma cells. At the same time, scientists kept intact the anti-invading powers of the T cell.
"His ability to kill, his ability to produce inflammatory proteins," said Roth, "we can exploit all of this and direct it exactly [target] we want it. "
Technology" really opens the door for us as a community to think of some very creative and potentially unique ways to activate a T cell, "said Ramsdell.
Herold said that it is too early to discuss the cost except to note that the therapies are not cheap. The current costs of gene therapy can reach $ 1 million for rare diseases. The treatment of more common diseases can also be expensive, with bills in the six figures.
Similarly, Ramsdell stated that it would be difficult to predict a timeline: "We will begin to see this kind of technology produced in human clinical trials"
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