The acronym, in itself, says little, CAR-T. But there is a lot behind this term in the challenge to tumors. In the future and beyond.
CAR-T stands for Chimeric Antigens Receptor T-Cells. And these are already very important realities. This is why it is essential to understand how these advanced therapies based on the modification and strengthening of T lymphocytes work, which they become capable of recognize and attack tumor cells.
We’re not talking about science fiction. These approaches are now a well-present reality in the clinical practice of numerous Italian centers. We are beginning to reap the fruits of these first years of use and management of CAR-T therapies, which have become a new treatment paradigm for some blood tumors, aggressive and refractoryand a reason for hope for patients after so many failures. But the journey into the future has only just begun.
How CAR-Ts work
CAR-Ts can be considered one step forward in personalized medicine in the field of tumors, and in particular neoplasms that affect blood cells. Today they represent a therapeutic option in those patients in whom previous standard therapeutic strategies (chemotherapy and haematopoietic stem cell transplantation) have failed. In practice we start from T lymphocytes taken from the patient’s blood. These, in the laboratory, are “armed” in such a way as to express the CAR receptor on their surface which helps them to recognize malignant cells and kill them, to then be reinfused into the patient himself.
In this sense, these therapies combine at least three fundamental aspects. First of all it’s really about care intelligentas they identify a target expressed by tumor cells while sparing the patient’s non-diseased tissues. Then they act directly on the immune system, therefore they must be included in theimmunotherapy. These are non-pharmacological treatments capable of modifying the drug resistance mechanisms that tumor cells implement in the most advanced stages of the tumor disease itself.
Finally, the cure comes through the cells. Moreover, from the same patient.
For this reason, these “specialized” units can remain in the body for a long time of the patient into which they are infused, guaranteeing a mechanism of action lasting over time and capable of reactivating every time the disease reappears. Let’s be clear. The use of these approaches, which truly represents a frontier in treatment, in rare cases can be linked to the risk of events such as cytokine release syndrome, which is caused by an excessive immune response due to the infusion of modified T lymphocytes . Additionally, reduction of B lymphocytes and antibodies and persistence of late cytopenia may occur. But we are still faced with one real innovationwhich is taking on ever greater space in therapy.
An immense development for a new frontier
While on the one hand the number of CAR-T cells authorized in oncology and onco-hematology is increasing (according to the 2019 Report of the European Society for Blood and Marrow Transplantation-EBMT on hematopoietic cell transplants, CAR-T therapies they grew by 650% compared to 2017) and in laboratories all over the world, scientific research is advancing rapidly in search of new and difficult targets to hit, CAR-Ts as we know them today are only the first step on a profoundly evolving path and with many questions to answer. And for this we need to know.
This is the meaning of the action of AIL – Italian Association against Leukemia, lymphoma and myeloma, which has decided to resume, from Milan, the CAR-T ‘Qvoyage’ – The future is already here”, a traveling and online campaign born in 2021, to inform patients, family members, caregivers and specialistsand improve knowledge, access and management of treatments, with an eye on the clinical experiences gained, the successes of treated patients and future areas of application.
When CAR-Ts are indicated
In Italy, according to very recent data, until today more than 1,400 patients were treated. This is a high number, bearing in mind that the first administration dates back to 2019 and that for a long period only one Center at the National Cancer Institute of Milan was authorized to carry out these treatments. Currently they are approx 30 authorized centres on the national territory and, of these, 10 in Lombardy. Experience in the use and management of CAR-T therapies is also gaining experience and evidence and clinical data are accumulating.
“Already today, approximately 50% of acute lymphoblastic leukemias and 40% of large B-cell lymphomas are cured by this therapy – explains Paolo Corradini, Director of the Hematology Division, Fondazione IRCCS Istituto Nazionale dei Tumori (INT) of Milan, Chair of Hematology, University of Milan and President SIE-Italian Society of Hematology – CAR-T cells are one of the most innovative and promising strategies for the treatment of refractory hematological diseases. There is a lot of real life data, deriving from the clinical practice of various Centers in different countries, which demonstrate how CAR-Ts work very well in follicular lymphoma, and equally well in multiple myeloma, although not with the same results as lymphomas. The response and survival data collected so far in refractory diseases are very encouraging, particularly for long-term survival. CAR-Ts prove that they work where nothing else was working.”
The stages of treatment
“CAR-T therapies have introduced into the panorama ofantineoplastic immunotherapy a revolutionary approach, which no longer involves the “simple” administration of a drug, but rather the proposal of a treatment program in sequential but distinct phases – reports Piera Angelillo, Hematologist, Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Hospital in Milan. Each of these phases involves highly complex processes and interdependent, which take place in physically distinct places, are managed by different teams and must take place at predefined times, requiring logistical work that sometimes goes beyond healthcare skills in the strict sense. The Centers authorized to administer CAR-T are units specialized in cellular and genetic therapies, where paths are standardized that guarantee the chain of custody and identity of the material from its collection to reinfusion. These paths are guaranteed by the Centre’s complex accreditation processes both at an extra-national and regional level”.
The infusion of CAR-T cells, for a patient who has experienced long and unsuccessful periods of treatment, rekindles hope but it is associated with fear regarding the unpredictable success rates or the possible failure of even this last treatment attempt. Psychological support, the constant presence of specialists and nurses, hospitality in the AIL lodging houses, are essential elements to help onco-haematological patients before, during and after receiving CAR-T therapy.
The opinion of patients
Research carried out with the support of Gilead and AIL Milano has made the point. “It was based on interviews with 12 patients and 7 caregivers, it investigated the main needs of onco-haematological patients subjected to CAR-T cells and their caregivers – says Sara Alfieri, Psychologist Researcher SSD Clinical Psychology, IRCCS Foundation National Institute of Tumors of Milan. Emerging as priorities are: so-called ‘existential’ needslinked to life and survival, or rather those needs for which the patient wants to be told, wants to believe and wants to hope that this umpteenth line of therapy will go well and that, if there is no positive result, there will be other therapeutic possibilities. Then the needs related to the desire to be emerge informed in a comprehensive, empathetic and sincere manner, otherwise, fears and uncertainties are fueled. Followed by care needs for which patients want the improvement of basic services (psychological support, visits and checks close to their residence) and the support of the world of associations to improve everyday life. The need not to feel abandoned is strong and predominant. For their part, caregivers show a more pessimistic outlook and are afraid to believe that yet another treatment attempt with CAR-T could have a happy ending.”
Even for children. Research, hope, futurethese are the key words of CAR-T cell therapy that is giving a future to the many children suffering from blood tumors, sometimes refractory, primarily acute lymphoblastic leukemia. Research activity in the pediatric field is intense and broad in order to find gene therapies with the best safety, efficacy and sustainability profile.
