by Elena Meli
Cellular therapy used against some blood tumors is now being taken into consideration, experimentally, for the treatment of some pathologies in which the immune system “misses the target”
Not just tumors: in the future of CAR-T there could also be the therapy of some autoimmune diseases. These cells of the immune system, extracted from the patient’s blood and genetically modified to become (almost) infallible snipers against tumor cells, are proving to be potentially useful for redirecting the immune response when it misses the target and attacks the body’s cells or tissues: the some studies have suggested this approach in adults with autoimmune diseases and this is confirmed by the first experiences on pediatric patients conducted by Franco Locatelli, director of the department of Oncohematology and Cellular Therapy, Gene Therapies and Hematopoietic Transplantation of the Bambino Gesù Hospital in Rome, where a clinical trial on the topic is starting in collaboration with Fabrizio De Benedetti, head of the Immunology, Rheumatology and Infectious Diseases research area.
The attack mechanism
The idea of using CAR-Ts in autoimmune diseases such as systemic lupus erythematosus or dermatomyositis derives from the fact that in these diseases B lymphocytes, after differentiating into so-called plasma cells, build antibodies which then attack healthy tissues and cells. «The Car-Ts developed for acute lymphoblastic leukemia and B-cell non-Hodgkin lymphomas attack CD-19, a protein expressed by the B lymphocytes that produce the damage in some autoimmune diseases», explains Locatelli. In tumors the number of CD-19 positive cells is very high and CAR-Ts are built to attack and eliminate them; in autoimmune diseases it can be of equal benefit to neutralize them, since B lymphocytes positive for the CD-19 molecule produce “wrong” antibodies against healthy cells and tissues.
Experiments on mice
Five years ago it was demonstrated that Car-T against CD-19 could reduce symptoms in experimental mice with a Lupus-like disease; in the same period, researchers from the Friedrich-Alexander University of Erlangen-Nuremberg, Germany, tested Car-T on a patient in very serious condition from systemic lupus erythematosus. The therapy was shown to reduce symptoms but also to cause fewer side effects than what was observed in patients treated for tumors and Locatelli specifies that «this better tolerability profile probably depends on the fact that in autoimmune diseases the number of B lymphocytes positive CD-19 is lower than that of leukemias and lymphomas.”
German researchers, after that first case reported three years ago in the New England Journal of Medicine, have treated pathologies such as systemic sclerosis or idiopathic inflammatory myositis; in December they reported good results in a patient with refractory myasthenia gravis.
The first three cases successfully treated in Italy
In Italy, thanks to the Officina Farmaceutica del Bambino Gesù in Rome which makes the preparation of Car-T possible, Locatelli’s team successfully treated three children with lupus or dermatomyositis. «The benefits are significant and were maintained in the following months: the disease parameters normalized and the immunosuppressive therapy was able to be suspended», he says. «A child with extremely compromised skin and muscle function, for example, today has healthy skin and can lead an active and normal life, in the face of a therapy for which a single administration is sufficient. CAR-Ts seem to reset the immune system: even when peripheral B lymphocytes reappear after a few weeks, the reactive component, responsible for the disease, does not re-emerge.”
The therapy was tried in patients who had failed conventional treatments and is complex, considering the procedures necessary to prepare the CAR-Ts: «For example, at Bambino Gesù we use protocols that do not involve freezing the cells, because the results improve» , specifies Locatelli. Avoiding freezing of lymphocytes is a positive factor also because the procedure is quicker and it takes 2 weeks to reach the treatment compared to around 4 for standard procedures.
The results
The results on the remission of autoimmune diseases and the benefits on the quality of life of patients give rise to hope: to summarize the effects, German researchers who are using CAR-Ts in adults recently recounted in Nature the experience of a man who, before cure he couldn’t walk 10 metres, whereas now he walks 10 kilometers a day. A tangible result in patients who are often children or young people. For now, the cases treated have been followed for a few months at most, so long-term considerations are premature, but the premises seem encouraging. «The scenario that is opening up is of great interest, especially for those who do not respond to standard therapies», concludes Locatelli.
The 3 Car-T therapies reimbursed in Italy
Since 2012, the year of its first application in humans, Car-T gene therapy has come a long way. Today in Italy three are reimbursed, for specific types of acute lymphoblastic leukemia and lymphoma and for patients in whom standard treatments, such as chemotherapy and/or transplant, have failed, but CAR-Ts are also effective in other blood tumors, like myeloma, and it was precisely in Bambino Gesù that important successes were achieved for the first time in a solid neoplasm, neuroblastoma. «Gene therapy offers concrete answers to patients who until recently were without hope, facing serious conditions, in a personalized and targeted way», says the president of the Bambino Gesù Hospital, Tiziano Onesti. “This medical revolution also promises to improve patients’ quality of life and reduce long-term costs associated with chronic disease management.”
What are Car-NKs instead?
The concept behind Car-T therapy is simple, in the case of tumors: the immune system always watches over the organism and also eliminates altered cells such as tumor cells thanks to T lymphocytes. A Car-T is a T lymphocyte trained to recognize a specific tumor in progress: the patient’s T cells are extracted from the blood and then reprogrammed in the laboratory with a viral vector that inserts the gene that codes for a protein (the Chimeric Antigen Receptor, hence the acronym Car) capable of recognize molecules on the surface of tumor cells.
Then the chimera cells are multiplied in vitro and reinfused into the patient to attack and eliminate the tumor. In addition to these traditional Car-Ts, today T cells are being created equipped with 2 receptors instead of 1, to engage tumor cells even better, and Car-NK, in which the Natural Killer lymphocytes are modified, which have the potential to reduce side effects and be recovered from an external donor to have ready Car-NK banks.
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February 3, 2024 (modified February 3, 2024 | 1:08 pm)
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