More than five years have passed since the arrival in Italy of the first anti -cancer gene therapy, the Car-t (acronym for Chimeric Antigens Receptor T-Cells). These advanced therapies are based on the modification and enhancement of T lymphocytes which in this way manage to recognize and attack cancer cells. And are proposed in different high specialization centers so as to represent a sort of New treatment paradigm for some blood cancersaggressive and refractory, and a source of hope for patients after many failures. In some ways, but there is still a lot to do and discover.
For this reason AIL – Italian Association against leukemias, lymphomas and myeloma, continues to carry on “Car-T-The future is already here “in order to spread knowledge on these therapies. To better understand what these treatments represent today and what they can involve in the future we try to collect today (and above all tomorrow) of science in six, simple questions.
What are car-t?
Technically, these are T -based therapies (particular lymphocytes) that express a chimeric receptor for antigen) are personalized innovative cellular therapies. Car-t cells are obtained through a genetic modification of the T lymphocytes of a patient who are made capable of recognizing cancer cells specifically. Car-t are part of the so-called advanced therapies and specifically are partly cellular therapies, as they use the patient’s T lymphocytes, partly gene, as T lymphocytes are genetically changed.
How do car-t work?
The concept is simple: fighting tumors “Armando” the immune system of the patient in order to induce a powerful immune response capable of recognize and eliminate cancer cells. Specific immune cells, T lymphocytes, are taken from the patient’s blood, genetically modified and grown in the laboratory to then be reinfused in the patient himself, ready to activate the response of the immune system against cancer. The Car-T technology was developed in the USA and the first treatment with these cells was performed in 2012 in the United States at the University of Pennsylvania, in a 7-year-old girl with acute lymphoblastic leukemia that became resistant to conventional chemotherapy treatments.
How do the Car-T are prepared and administered?
The procedure that leads to the realization of the Car-T is made up of a complex procedure in several stages: withdrawal of the patient lymphocytes, genetic engineering, pre-treatment with patient chemotherapy, infusion and monitoring.
The withdrawal It represents the first step of the car-t production takes place in the transfusion centers authorized for the collection of leukocytes. There collection It is called Leucoferesi and allows to isolate leukocytes from the blood of patients through a cell separator. The leukocytes thus obtained are sent to the workshops (cell factories), highly specialized and certified by the competent authorities to carry out genetic manipulation and the expansion of the cells.
The second phase provides for the so -called Genetic engineeringA: patient lymphocytes are genetically modified and activated through the introduction of a recombinant gene that is transported by an inactivated virus within the nucleus. This manipulation induces the expression on the surface of the lymphocytes of the chimeric receptor of the antigen (car), thanks to which the modified T lymphocytes are able to recognize a specific antigen present on the surface of the cancer cells and bind to them.
The third step is based on Preparation of the patient: Before the infusion of the Car-T cells, the patient is hospitalized and subjected to a chemotherapy that aims to break down the number of circulating lymphocytes, induce the production of some specific growth factors for lymphocytes. In this way, genetically modified T lymphocytes will be able to expand quickly in the patient’s body. At this point we proceed to‘infusionwith Car-T cells that are infused as it happens in case of blood transfusion. And then you arrive at monitoring: After the infusion, the patients remain hospitalized in the center who made the infusion for a few days (or weeks) for monitoring health conditions and any adverse events.
What can be treated with the car-t?
Car-t therapies are the first form of gene therapy approved for different pathologies, albeit in extremely selected cases. In this sense, they can be used for the treatment of the acute refractory or in relapse of pediatric and young adult patients up to 25 years and some aggressive forms of non -Hodgkin lymphoma in advanced phase. The Car-T represent a therapeutic option in those patients in whom the previous standard therapeutic strategies (chemotherapy and transplantation of hematopoietic stem cells) have failed.
How effective and safe car-t are?
Car-t therapies compared to conventional therapies can allow to obtain Complete remissions also in the phase of very advanced disease. In the clinical studies evaluated for the purpose of the marketing authorization (AIC) of the Car-T therapy for acute lymphoblastic leukemia with refractory B cells, in post-transplant recidivism or in second or further recurrence, 81% of patients obtained a complete remission of leukemia. For the treatment of diffuse large B-cell lymphoma and primitive lymphoma of B cells B after bankruptcy of two or more systemic therapy lines, in clinical studies it was observed that 40-47% of patients who received Car-T therapy have obtained a complete remission of lymphoma. However, much still remains to be understood and to study with respect to the safety and effectiveness of these treatments whose use is associated with the risk of sometimes serious events, such as cytokines release syndrome, neurological toxicity. reduction of B lymphocytes and antibodies.
Where do the Car-T are administered?
Car-t therapies can be administered in a Limited number of hematology and onco-hematology centerspediatric and for adults, with high specialization for the treatment of leukemias and lymphomas, with specific requirements (including the availability of access to intensive care) and authorizations for cellular therapies. In Italy there are currently 44 centers specialized in hematology and onco-hematology in which Car-T infusions identified by the regions are carried out on the basis of the requirements and the characteristics provided for by law:
- the certification of the National Transplant Center in accordance with the EU directives;
- Jacie 7.0 accreditation for alloenic transplantation;
- the presence of a center of apheresis and a laboratory for cryoprew with qualified and adequately trained staff;
- The availability of an intensive care unit and the presence of a multidisciplinary team appropriate to the patient’s clinical management and possible complications.
