CAR-T cell therapies

Content

Introduction

Introduction

The term CAR-T is an acronym deriving from the English (Chimeric Antigen Receptor T-cell) and literally means "T cells with chimeric receptor for the" antigen. "The term refers to a type of immune system cell, T lymphocytes, taken from a person with cancer and genetically modified in the laboratory to make them capable of attack the tumor once re-infused into the same person from which it was taken CAR-T represent an innovative, but extremely complex, approach in the fight against cancer.

The strategy aims to enhance a mechanism present in the immune system: the ability of a particular type of cell, cytotoxic T lymphocytes, to attack abnormal cells of the organism (for example because they become infected or because they have become malignant). The lymphocytes recognize infected cells or malignant because these have antigens on their surface, ie fragments of viruses or bacteria in the case of an infected cell or of tumor proteins in the case of a malignant cell, not present in normal cells. lymphocytes occurs through a specific receptor present on the cell surface of the lymphocyte itself, which adapts perfectly to the antigen, just like a key adapts to its lock.

In the laboratory production of CAR-T cells, the lymphocyte receptor is modified in such a way that it recognizes the antigens present on the tumor cells and transmits an activation signal to the lymphocyte to eliminate them. Due to this dual function, the new receptor is called chimeric.

How CAR-T cells are generated

How CAR-T cells are generated

Unlike traditional drugs, CAR-T cells are so-called "advanced therapy medicinal products" (PMTA) and are generated in a personalized way or using the blood of the person undergoing the therapy. Precisely for this reason, CAR-T cells represent a much more complex type of drug, with very high costs and problems relating to the method of production.

The production of CAR-T cells is performed in highly specialized and controlled facilities, called pharmaceutical workshops for cell therapies. From the blood taken from the patient undergoing the therapy, the T cells are separated from the remaining blood cells. This procedure is called leukapheresis. The isolated T cells are then genetically modified to have on their surface the chimeric CAR receptor which recognizes the antigen of the tumor to be treated. The T cells thus obtained are amplified in the laboratory to increase their quantity and then, after passing the controls which guarantee the safety and quality of the product obtained, are administered to the patient.

A simple schematic on the process of generating CAR-T cells can be found at this link.

Side effects

Side effects

CAR-T cell therapy can cause significant undesirable effects (side effects) in about a quarter of people treated. Among the most common reactions are:

  • cytokine release syndrome, a condition which can cause fever, vomiting, pain, low blood pressure and which, if not controlled, requires hospitalization in intensive units and can even lead to death
  • encephalopathies, with migraines, drowsiness and mental confusion
  • bacterial or viral infections

Fortunately, there are therapies available to reduce the severity of side effects by using different drugs; for example, a drug used to treat arthritis (Tocilizumab) has been shown to significantly reduce the extent of cytokine release syndrome.

The authorized CAR-T therapies

The authorized CAR-T therapies

So far the EMA (European Medicines Agency) has authorized two therapies with CAR-T cells (axicabtagene ciloleucel and tisagenlecleucel) which in both cases recognize the CD19 antigen, present in various blood cancers.

Axicabtagene ciloleucel is licensed as a treatment for adults with very aggressive non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma or primary mediastinal large B cell lymphoma. For both of these cancers, CAR-cell therapy T can only be undertaken after the patient has undergone at least two established therapies (not innovative such as CAR-T cells) and these have ceased their therapeutic effect.

Tisagenlecleucel is approved for children and young adults up to 25 years of age with refractory B-cell acute lymphoblastic leukemia (i.e. that does not improve with established therapies) or relapse (which reappears after transplantation or more than twice after treatment). Additionally, the drug was approved for adults with diffuse large B-cell lymphoma after other established treatments failed to prove more effective.

Both therapies require a preventive treatment with chemotherapy (which must take place before the administration of the CAR-T) to favor the persistence and growth of the administered cells.

CAR-T therapies being tested

CAR-T therapies being tested

In light of the encouraging results obtained during clinical trials on approved therapies, numerous trials are currently underway on new therapies with CAR-T cells in Italy and around the world. With these experiments we try to obtain a more lasting efficacy, increase the safety of the therapy, broaden the spectrum of tumors to be treated, and simplify the production process.

In-depth link

In-depth link

European Medicines Agency (EMA). Kymriah (English)

European Medicines Agency (EMA). Yescarta (English)

National Institute of Health (NIH), National Cancer Institute. CAR T cells: engineering patients "immune cells to treat their cancers (English)

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