Home Health Cancer: How Car-T Gene Therapy Works

Cancer: How Car-T Gene Therapy Works

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Cancer: How Car-T Gene Therapy Works

Amily Whitehead looks like an ordinary 16-year-old today, but she has written medical history. In 2012 she was seven, for two years she had been struggling with acute lymphoblastic leukemia against which nothing seemed to work. She arrived at the Children’s Hospital of Philadelphia the day after the approval of 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 ten years free from cancer.

“Emily had a strong reaction to the therapy, we were afraid of losing her. If that had happened, the study would have been stopped and the Car-T would have remained a utopia for a long time to come, ”said Carl June, the director of the Pennsylvania University Immunotherapy Center, who treated the child in early May, recalling those days. It didn’t happen, Emily was healed. And today the Car-T are more than a hope for many sick people.

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

Modified cells. Genetically modified T lymphocytes are making cancer therapies increasingly effective and personalized. Car-T are obtained in the laboratory from the patient’s T lymphocytes, extracted with a sample and genetically modified. The modification, implemented through a viral vector, inserts the Car receptor gene (Chimeric Antigen Receptor) into these lymphocytes, a protein capable of recognizing specific structures present on the surface of the tumor. The modified cells, obtained in this way, are then multiplied in vitro and reinfused into the patient, ready to attack and eliminate the tumor

The idea of ​​redirecting T lymphocytes to a specific tumor target dates back to about thirty years ago, when Zelig Eshhar, an immunologist at the Israeli Weizmann Institute of Science, first made a Car-T: the pioneering study dates back to 1993 but how explains Franco Locatelli, director of the Department of oncohematology and cell therapy, gene therapies and hematopoietic transplantation of the Bambino Gesù Hospital in Rome: «Those first generation Car-T’s didn’t work. The turning point came with the second generation of modified lymphocytes, capable of recognizing the tumor protein and at the same time activating, killing the target cell ».

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Gene therapy. It didn’t happen in a snap of fingers, it took twenty years to fine-tune Car-T for use in humans. Then in 2012 the success on 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. Emily was even received by the then President of the United States Barack Obama, as a testimonial of the personalized medicine of the future.

Car-T therapies have been shown in the field to be effective even in patients with no other options for treatment, recording 30-40 percent complete remissions in the most complex cases. They are hyper-personalized therapies, because the active principle is built from time to time with the patient’s cells. From the point of view of approval, they are managed like drugs: in 2019 the first Car-T received the green light in Italy and today there are three therapies reimbursed by the National Health Service, for specific types of acute lymphoblastic leukemia and lymphoma and for patients in whom standard treatments, such as chemotherapy or transplant, have failed.

The potential of the Car-T. The centers authorized to administer them are about thirty and must guarantee precise requirements, because therapy with Car-T cannot be improvised and as emphasized by Benedetto Bruno, director of the University Hematology Division at the Department of Molecular Biotechnology and Health Sciences of the University of Turin «it is not a road for everyone. The patient’s T lymphocytes, for example, may be inefficient or in inadequate numbers. Furthermore, between the collection of T cells and their reinfusion, there are three to four weeks: for some, the progression of the disease can be so rapid as not to allow such a wait. In a good percentage of cases the tumor is eradicated, but in at least half of the patients the response can only be transitory: the potential of Car-T is great, but we must not believe that they are a panacea ».

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Also because it is necessary to consider the possible side effects, especially the neurological toxicity associated with the infusion of immune cells and the cytokine release syndrome, a generalized reaction due to a storm of inflammatory molecules, which can be very serious and is the one that caused seriously endangers the life of little Emily. These are known problems and, as Locatelli observes, «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 the enzyme lactate dehydrogenase, the likelihood of a good response to chemotherapy is low, while the ability to respond to Car-T therapy is not affected: this can help select patients to be initiated earlier on treatment with modified lymphocytes. The Child Jesus, for example, participates in a European study that is verifying whether the effectiveness of Car-T can be higher by treating children who are in their first relapse or have negative tumor characteristics that predict a poor response to other therapies “.

Thus, while in Italy about 500 patients are already treated per year, many studies are underway to refine the knowledge on Car-T, create new ones, expand its use on other cancers (for example, for the multiple myeloma): “At the moment there are about eight hundred clinical trials in the United States and China alone,” informs Bruno. In short, research gallops to have Car-T ever more targeted and powerful.

Non-Hodgkin’s lymphoma. “For example, T lymphocytes are being tested modified not with genes derived from mice, like the current ones, but with human DNA: they seem more effective,” says Locatelli. ‘Another approach is to equip T cells with two receptors instead of one: therapy often fails because the target cancer cells stop expressing the protein that is recognized and attacked by Car-T. If there are two receptors, the likelihood of the tumor escaping is reduced. Immune cells other than T lymphocytes could also be used, such as natural killer (Nk) lymphocytes, which have the potential to reduce side effects and could be recovered from an external donor ».

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It’s not science fiction: Katy Rezvani, of the University of Texas 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 eleven patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia without observing the usual side effects of Car-T; in eight cases there was a response, in seven a complete remission.

Excessive costs. While you are thinking about the future, however, you have to face the boulder of costs: for a treatment with Car-T you can spend up to 300,000 euros. “It should be noted that if the therapy is successful and the disease is eradicated, the use of other drugs is spared, which are also very expensive for cancers for which Car-T are approved,” says Bruno. “In short, it is not easy to evaluate the real cost-benefit ratio and it all depends on the moment in which the treatment is applied and therefore on which other therapies are avoided: continue to study the Car-T to get the most out of it, administering them to each patient when it is more appropriate, it is a way to make them more and more sustainable ».

The other is to learn 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 routes are being investigated involving the use of fresh, locally treated T lymphocytes. The Bambino Gesù is being done at the hospital’s pharmaceutical workshop and eleven children have already been involved in the phase I / II clinical trial underway. “Avoiding lymphocyte freezing is a positive factor, plus the procedure is faster and for some patients time can be a deciding factor. The results to date are comforting: in all the little ones there has been an answer », concludes Locatelli.

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