This was discovered by a group of researchers from the IRCCS San Martino Polyclinic Hospital in Genoa, engaged at the forefront of research into innovative cell therapies against blood cancer. The results of the study recently published in the Journal of Neuroimaging, result of the synergy of the departments of Hematology, Cell Therapy, Nuclear Medicine and Clinical Neurology, show that the use of cerebral PET allows early identification of the traces relating to the two most frequent and most serious complications of frontier CAR-T therapy: the syndrome from cytokine release and CAR-T related neurotoxicity affecting the majority of treated patients with often fatal outcomes. This will make it possible to have a biomarker available which makes it possible to identify patients most at risk and outline a more suitable alternative therapy for them.
Rome, Friday 28 July 2023 – Five more minutes. It is enough to add to the time of a total body PET, a routine examination for cancer patients with large B-cell lymphoma, to search the brain with a simple brain scan, useful clues to detect the possible onset of serious side effects related to the ‘innovative cell therapy. For the first time, a group of researchers from the IRCSS Policlinico San Martino Hospital in Genoa has identified a possible prognostic biomarker of the two most common and serious complications of CAR-T therapy, cytokine release syndrome (CRS) and CAR neurotoxicity -T correlated (ICANS), which affect most of the patients treated, with sometimes fatal outcomes that worry the experts involved in evaluating not only the efficacy but also the safety of the new treatment.
“Through the PET images of the brain we have identified a specific signature, linked to cerebral metabolism, indicative of the presence of CRS and ICANS – underlines Silvia Morbelli, co-author of the study, medical researcher of the Nuclear Medicine Unit of the IRCCS San Martino Policlinico Hospital in Genoa and associate professor of Nuclear Medicine at the University of Genoa -. The identification of this signature is invaluable – continues Morbelli – because it potentially allows us to more effectively select patients for whom CAR-T therapy presents greater risks of neurotoxicity. And if confirmed in subsequent studies, it could serve as an early and prognostic biomarker”.
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CAR-T CANCER TREATMENT
CAR-T (Chimeric Antigen Receptor) therapy is a revolutionary treatment that uses cells of the immune system that are suitably trained to recognize and fight cancer.
It is considered the future of the fight against cancer and was approved by AIFA three years ago for patients with diffuse large B-cell lymphoma and acute large B-cell leukemia who do not respond to other therapeutic options.
“CAR-T cell therapy uses the patient’s own T lymphocytes, one of the most important cells of the immune system, as a cure. Such lymphocytes – explains Emanuele Angelucci, co-author of the study and Director of the Hematology and Cellular Therapies Unit of the San Martino Polyclinic Hospital in Genoa they are extracted from a sample of white blood cells and, through a virus, a gene is inserted into their DNA which causes a protein to appear on the surface of the lymphocyte which acts as a ‘key’ to recognize cancer cells.
Once reinfused, the cells taken from the patient’s blood are able to recognize a protein that is expressed on the tumor cells which is then attacked”.
“It is a frontier treatment for blood cancers arising from mutations of B lymphocytes, such as in the case of lymphoma, which has demonstrated high efficacy thanks to its early action and improved survival rate – continues Angelucci -. In 2021, around 200 procedures were performed in Italy, but the number of patients treated with CAR-T is progressively increasing. We are now traveling on several hundred cases a year and San Martino di Genova is a national reference point and the only center in Liguria enabled for the use of CAR-T cells. And since the end of 2020 we have administered 46 therapies”.
THE MOST COMMON SIDE EFFECTS: CRS AND ICANS NEUROLOGICAL SYNDROMES
“However, these new therapies, which have great potential, carry risks of serious, sometimes fatal complications developed by the majority of patients – says Angelucci –. One of the most likely side effects is CRS cytokine release syndrome, characterized by an uncontrolled systemic inflammatory reaction. A veritable storm of cytokines triggered by the activation of T lymphocytes. CRS affects about half of patients undergoing CAR-T therapy and generally occurs a few days after reinfusion. The symptoms are fever, low blood pressure and chills, even leading to fatal outcomes, if not known and treated immediately “.
If CRS occurs in the majority of patients, about one-third develop a second syndrome that is also life-threatening, called CAR-T therapy-related neurotoxicity syndrome.
“ICANS is a still very little known syndrome of neurological toxicity and the term is extremely generic because its origin and mechanism are not yet well known – Angelucci points out -. The symptoms are the most varied from a neurological point of view, loss of consciousness, convulsions, tremors possibly preceded by cognitive disorders of various types, sometimes even in writing”.
I STUDY
The study involved 21 patients with large B-cell lymphoma and undergoing CAR-T therapy.
16 developed cytokine release syndrome, which in 5 cases was followed by the onset of CAR-T related neurotoxicity. The researchers compared the brain PET scans of the patients, using specific algorithms, and discovered the presence of specific traces of the metabolic distress condition, called hypometabolism, in patients with CRS and ICANS.
“To the total body PET examination we associated it with a scan dedicated to brain acquisition and with software we evaluated the metabolism of the brain – observes Morbelli -. From the comparison with patients suffering from cytokine release syndrome and patients who had not developed complications, it emerged that patients with CAR-T neurotoxicity had areas of metabolic suffering much more extensive than those without CRS and more localized in the cortex front”.
“This effectively gives us a biomarker that makes this clinical aspect objective and which, potentially, can allow us to understand who is more prone to developing these complications and to outline the most suitable alternative treatment – conclude Morbelli and Angelucci -. These findings could be extended to all CAR-T-treated patients who are growing rapidly.”
NurseTimes editorial team
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