In just over 10 years, CAR-T has revolutionized the treatment of some of the most terrible blood cancers. Despite the successes that it continues to accumulate, it inevitably also presents limitations, and cannot be used on every type of neoplasm. But the room for improvement for cell therapies is still wide.
A new study by San Raffaele in Milan reveals the potential of a different approach, which allows T lymphocytes to be transformed into weapons against acute myeloid leukemia, through the engineering of a particular type of receptors known as TCR (or T Cell Receptors).
The research, just published in Science Translational Medicine, born from the work of two Italian scientists: Chiara Bonini, professor of Hematology of the Vita-Salute San Raffaele University, and Eliana Ruggiero, researcher in her laboratory and first author of the new study.
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The choice to focus on acute myeloid leukemia is not accidental. It is in fact a hematological neoplasia that can occur in very different forms, and for those at high risk, which quickly give rise to relapses and are resistant to standard therapies, the therapeutic options are unfortunately still quite limited. For now, CAR-T is struggling to find space in the treatment of this tumor, because it produces excessive toxicity and fails to prevent recurrence. This is why the San Raffaele researchers decided to try a different way to arrive at a new cell therapy against this pathology.
The difference between CAR-T and new cell therapy
In CAR-T therapies, patients ‘ lymphocytes are taken and modified with the addition of an artificial receptor that identifies a protein present on the membrane of cancer cells, so that, once reinfused, they attack the neoplasm. The therapy developed at San Raffaele does the same, but using a different type of receptors, called TCR, which allow to identify fragments of proteins also present inside a cell. “TCR receptors are very powerful and versatile tools-explains Ruggiero-with these receptors, in fact, the engineered lymphocytes are able to identify a tumor cell not only based on the surface proteins it possesses (as in the case of CAR-T therapies), but also for the proteins or other types of molecules that are present inside it”.
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The Targett
The therapeutic benefits are remarkable: a greater number of neoplasms can be treated, and it is easier to target proteins essential for the survival of the tumor, reducing the chances that the disease can develop resistance to the therapy. Those chosen by the San Raffaele researchers are receptors capable of identifying a protein known by the abbreviation W To obtain them, the scientists selected lymphocytes with a greater ability to recognizet T1 in the blood of healthy donors, identified the gene that codes for the production of their TCR receptors, and inserted it into another T lymphocyte using Crispr-Cas9, a very precise “DNA cut and sew” technique (gene editing) developed in recent years.
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Harnessing immune memory
Since these receptors are physiologically present on human lymphocytes, this approach has an additional advantage over CAR-T: the therapy is able to activate the body’s immune memory and could therefore more effectively protect patients from the risk of recurrence, keeping the immune system alert in case the tumor makes its appearance again. “In our study we tested the efficacy of engineered lymphocytes on in vitro and in vivo models, and we achieved very good results,” Bonini says Health. “Thanks to the partnership we have established with Intellia Therapeutics, a very strong company in Crispr-Cas9 technologies, our technique has all the credentials to become a real therapy, and in fact a clinical trial has already started in America that will evaluate its safety and effectiveness on patients with acute myeloid leukemia”.
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Prospects in solid tumors
The results of the trial are expected to arrive within a couple of years, and if they prove positive the new TCR engineered lymphocyte therapy could be available to patients relatively quickly. In the meantime, of course, researchers are already working to further improve the possibilities of this new therapeutic approach. “One of the greatest limitations in the use of TCR receptors is that patients must have an immune system compatible with that of healthy donors for them to function, “concludes Bonini:” to start, we chose a receptor that should fit more or less in 40% of patients eligible for therapy. However, we are already working to isolate receptors that are also compatible with other groups of patients, and also to find other therapeutic targets. A very promising field, for example, is that of solid tumors, on which it is more difficult to use CAR-T effectively and towards which TCR receptors, which also recognize proteins present within cancer cells, could be more effective”.
Image credits: IRCCS San Raffaele Hospital, Milan