Another step forward, made thanks to Italian research, will make Car-T safer for patients with lymphoma without slowing down treatment times too much. In fact, it only takes five more minutes to identify patients at risk of serious side effects thanks to a brain PET. 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.
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Car-T treatment
Therapy with Car-T (Chimeric Antigen Receptor) uses suitably ‘trained’ cells of the immune system to recognize and fight the tumour. 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 – he explains Emanuele Angelucci, co-author of the study and Director of the Hematology and Cellular Therapy Unit of the San Martino Polyclinic Hospital in Genoa – are extracted from a sample of white blood cells and, through a virus, a gene is inserted into their DNA which causes surface of the lymphocyte a protein appears 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”.
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Hundreds of patients treated with Car-T
It is a frontier treatment for blood cancers that arise from mutations of B lymphocytes, as in the case of lymphoma. “The Car-T therapy – continues Angelucci – has demonstrated high efficacy thanks to the early action and the improvement in the survival rate. In 2021, around 200 procedures were performed in Italy, but the number of patients treated with Car-T is progressively increasing. Now we are 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”.
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Potential side effects of Car-T
Like all therapies, CAR-T also carries risks of serious, sometimes fatal complications, developed by most patients. “One of the most probable side effects – says Angelucci – is the 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 “.
Neurotoxicity syndrome
If CRS occurs in the majority of patients, about one-third develop a second syndrome, which is also potentially fatal, called Car-T therapy-related neurotoxicity syndrome. “It 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”.
The role of the brain pet
For the first time, a group of researchers from the IRCSS San Martino Polyclinic Hospital in Genoa has identified a possible prognostic biomarker of these two serious complications of Cra-T therapy. researchers have discovered that adding to the total body PET that is routinely performed for cancer patients with large B-cell lymphoma, even a brain PET can be searched in the brain with a simple brain scan, useful clues to detect the possible onset of serious side effects.
“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 – he underlines Silvia Morbelli, co-author of the study, medical researcher of the Nuclear Medicine Unit of the IRCCS Policlinico San Martino Hospital in Genoa and associate professor of Nuclear Medicine at the University of Genoa -. The identification of this signature is very precious – 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”.
The Italian study
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, involved 21 patients with large B-cell lymphoma and subjected to Car-T therapy, of which 16 developed cytokine release syndrome, which in 5 cases was followed by the appearance of Car-T related neurotoxicity. The researchers compared the patients’ brain PETs, using specific algorithms, and discovered the presence of specific traces of the condition of metabolic suffering, called hypometabolism, in patients with CRS and ICANS. “From the comparison with patients affected by cytokine release syndrome and patients who had not developed complications – observes Morbelli – 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 frontal cortex”.
Possible solutions also for other patients
Thanks to the biomarker it will be possible to understand who is more prone to developing these complications and therefore to outline the most suitable alternative treatment. “These results – conclude Morbelli and Angelucci – could be extended to all patients treated with CAR-T who are growing a lot”.