Cancer: How does Car-T . gene therapy work?

Today, Amelie Whitehead looks like an ordinary 16-year-old, but she wrote a medical history. In 2012, he was seven years old, and for two years had been suffering from acute lymphoblastic leukemia that didn’t seem to be working. She arrived at Children’s Hospital of Philadelphia the day after they approved the use of Car-T cells in a human clinical trial: She was the first patient to receive them and on May 10 she celebrated 10 years cancer-free.

“Emily had such a strong reaction to the treatment, we were afraid of losing her. Remember those days,” said Carl John, director of the University of Pennsylvania Immunotherapy Center, who treated the child in early May. It didn’t happen, Emily was cured. Today Car-T is More than just hope for many patients.

The basic concept is simple: the immune system constantly monitors the body and also eliminates mutating cells such as cancer. If T lymphocytes, the “warriors in the field”, were genetically engineered to recognize and attack a tumor, diseased cells could be doomed. Car-T is just that: an externally trained lymphocyte.

modified cells. Genetically modified T lymphocytes make cancer treatments increasingly effective and personalized. Car-T is obtained in the laboratory from a patient’s T lymphocytes, extracted from a sample and genetically transformed. The modification, which is carried out through a viral vector, introduces the vehicle receptor gene (chimeric antigen receptor) into these lymphocytes, a protein capable of recognizing specific structures located on the surface of the tumor. The modified cells, obtained in this way, are then multiplied in the laboratory and reintegrated into the patient, ready to attack and eliminate the tumor.

The idea of ​​redirecting T lymphocytes to a specific tumor target dates back nearly thirty years, when Zelig Ishar, an immunologist at Israel’s Weizmann Institute of Science, first prepared Car-T: The groundbreaking study dates back to 1993 but how Franco Locatelli explains, Director of the Department of Oncology, Cell Therapy, Gene Therapies and Blood Component Transplantation at the Bambino Gesu Hospital in Rome: “These first generation Car-T did not work. The turning point came with the second generation of modified lymphocytes capable of recognizing the tumor protein while simultaneously activating and killing the target cell.”

Gene therapy. Not in a jiffy, it took twenty years to fine-tune the Car-T for use in humans. Then in 2012, the success of Emily, hailed as one of the biggest advances in immunology and cancer treatment, paved the way for this gene therapy that sparked so much hope. Even then-President of the United States Barack Obama greeted Emily as a sign of future personalized medicine.

Car-T therapies have been shown to be effective in this area even in patients without other treatment options, with 30-40 percent of complete remissions reported in the most complex cases. They are highly personalized treatments, because the active principle is built from time to time with the patient’s cells. From an approval point of view, they are administered like medicines: in 2019, the first Car-T received the go-ahead in Italy, and today there are three treatments reimbursed by the National Health Service, for specific types of acute lymphoblastic leukemia and lymphoma of patients for whom standard treatments have failed, Such as chemotherapy or an organ transplant.

Car-T capabilities. The centers authorized to operate them are about thirty years old and must ensure exact requirements, because treatment with Car-T cannot be improvised and as emphasized by Benedetto Bruno, Director of the University’s Department of Hematology in the Department of Molecular Biotechnology and Health Sciences at the University of Turin “It is not a path for everyone. For example, a patient’s T lymphocytes may be ineffective or in insufficient numbers. Moreover, between the collection and reintegration of T cells, there are three to four weeks: for some, disease progression can be too rapid to allow such a wait. In a good proportion of cases the tumor is excised, but in at least half of the patients the response can be temporary: the potential of Car-T is great, but we must not believe that it is a panacea.”

Also because it is necessary to consider the potential side effects, especially the neurotoxicity associated with the injection of immune cells and the cytokine release syndrome, a general reaction due to a storm of inflammatory molecules, which can be very dangerous and which has put little Emily’s life in grave danger. These are well-known problems, and as Locatelli notes, “Today we know better the elements that predict a positive response to treatment.

Against lymphomas. For example, we know that in patients with lymphomas and elevated levels of lactate dehydrogenase, the likelihood of a good response to chemotherapy is low, while the ability to respond to Car-T treatment is not affected: this can help select patients to start early. in modified lymphocyte therapy. For example, Baby Jesus is participating in a European study that is investigating whether the efficacy of Car-T can be higher by treating children who have a first relapse or have negative tumor characteristics that predict poor response to other treatments.”

Thus, while about 500 patients are already treated in Italy annually, several studies are underway to improve knowledge about Car-T, create new ones, and extend its use to other cancers (for example, for multiple myeloma): “In there are about Eight hundred clinical trials in the United States and China alone. In short, research is accelerating to make the Car-T more targeted and powerful.

Non-Hodgkin’s lymphoma. “For example, modified T lymphocytes are being tested not with mice-derived genes, like the current ones, but with human DNA: it seems more effective,” Locatelli says. Another approach is to provide T cells with two receptors instead of one: treatment often fails because the target cancer cells stop expressing a protein that Car-T recognizes and attacks. If there are two receptors, the tumor is less likely to escape. Immune cells other than T lymphocytes, such as natural killer (Nk) lymphocytes, which have the potential to reduce side effects and can be recovered from an external donor, can also be used.”

It’s not science fiction: Katie Rezvani, of the University of Texas MD Anderson Cancer Center, has shown that it is possible to create Car-Nk by taking lymphocytes from the umbilical cord and reprogramming them. Rezvani tested Car-Nk on 11 patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia without noticing the usual side effects of Car-T; In eight cases there was a response, in seven cases complete remission.

Expensive costs. As you think ahead, you must face the rock of costs: for a treatment with a Car-T, you can spend up to 300,000 euros. “It’s worth noting that if the treatment is successful and the disease is eradicated, then other drugs will not be used, which is also very expensive for the cancers that are approved to treat,” Bruno says. “In short, it is not easy to assess the true cost-benefit ratio and it all depends on the moment the treatment is applied and thus avoiding other treatments: continue to study Car-T to get the most out of it, and administer it to each patient when it is most appropriate, it is a way To make it more and more sustainable.”

The other is learning how to produce them “at home”: Today, T-lymphocytes must be frozen and sent elsewhere, often to the United States, to be modified in certified laboratories. But alternative approaches are being investigated, including the use of fresh, locally processed T lymphocytes. Bambino Gesù is being performed in the hospital’s pharmaceutical workshop and 11 children have already participated in the ongoing Phase I/II clinical trial. “Avoiding freezing of lymphocytes is a positive factor, in addition to the fact that the procedure is faster and for some patients the time can be a decisive factor. The results so far are reassuring: there was an answer in all the young ones”, concludes Locatelli.

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