The hope of CAR-T, living drugs against cancers

Decoded content
16/10/2018

The development of CAR-T, cells in our immune system modified to target some types of cancer, has ushered in a new era for therapies based on the adaptability of the living cells.

Chimeric Antigen Receptor T cells (yellow) next to a cancer cell

 

CAR-T cells represent a revolutionary type of therapy that has been attracting a lot of media attention since 2017 when the FDA (the health authority that controls and authorises the marketing of drugs in the United States) approved their use against acute lymphoblastic leukaemia in children and advanced lymphoma in adults. Initially, they helped to treat those leukaemias that were not responding to other treatments available, and within record time. However, it is their mechanism of action which is of great interest to clinical research because an entirely new class of therapy is instructing our natural defence system and guiding it towards our chosen target, including cancer cells that had previously not been concerned by the immune system.

 

The key tool in the process is the T cell, a white blood cell (or lymphocyte) that plays a major role in our immune defence. When a pathogen (virus, bacteria or other foreign body) is identified in the body, the T cells actually adapt their external receptors so they are able to recognise and destroy it quickly. Receptor rearrangement is a major advantage as it makes T cells effective against all types of pathogens, even those the human body has never come across before. The pathogen binding by the T cell receptors triggers the release of molecules the open the membrane of the enemy cell, while others enter and kill it. In addition, the T cell with its specific receptors then multiplies to create an “army” of cells that target the foreign body.

 

Feat of molecular engineering

It was researchers at the Weizmann Institute in Israel who came up with the idea in 1989 of artificially modifying the external receptors of a natural T cell so that it could target cancer cells. The success of this feat of molecular engineering paved the way for customized therapies.

 

Samples of T cells that act as base material for this laboratory handling are taken from the blood, either of the actual patient – in which case, we talk of “autologous” treatment – or of a healthy donor – in which case, we talk of “allogenic” treatment.

The T cell modified in the laboratory is then cultured so that it can multiply in vitro. A large number of identical T cells can then be obtained, which are injected into the patient where they continue to multiply while binding to the cancer cells they have been programmed to recognise and destroy.

 

Challenges to overcome

With this approach, we introduce a partially artificial element (the modified T cell) into a very complex living environment, which can lead to unexpected consequences:

 

  • T cells can also destroy other cells in the organism, therefore creating illnesses in which the immune system attacks its own organism.
  • The elimination process of cancer cells by T cells can lead to a toxic syndrome and other organs like the liver, kidneys or nervous system can be affected.
  • Until now, these therapies were only effective against blood cancers, leukaemias or lymphomas. In the long term, we hope to use them for “solid” tumours located in the tissues.

 

With CAR-T cells, it has been proven that a living cell of the immune system can be modified and made into a specific therapeutic tool. This is a first stage in harnessing and developing our natural defence system to create personalized programmable therapies that use the versatility and efficiency of the immune system.

 

And what about Servier?

The R&D Department of the Servier Group launched a research programme in 2015 in collaboration with Cellectis to develop UCART19, an allogenic CAR-T cell for the treatment of leukaemias carriers of the CD19 antigen. UCART19 is currently in phase I study for the treatment of acute lymphoblastic leukaemias in children and adults.