In recent months we have written a number of posts on the progress being made in the development of chimeric antigen receptor T cell (CAR-T) therapies:
- The NHS gets on the bandwagon with CAR-T
- Can’t stop the CAR-T
- Side CAR-Ts
- CAR-T rolls on
With two therapies already on the market and many more in the pipeline, this exciting new treatment is understandably grabbing the headlines. However, CAR-T therapy is by no means the whole story and there are a number of related immunotherapies in the pipeline.
Gene modified TCR therapy
One of the most well-known among these alternative types of immunotherapies is gene modified T cell receptor (TCR) therapy. In CAR-T therapy, naturally occurring T cells are engineered to express chimeric receptors on their cell surface. The external portion of these artificial receptors is made up of an antibody that directs the T cells to recognise specific cancer cells. Like CAR-T therapy, gene modified TCR therapy also works by redirecting T cells to target tumours. However, instead of engineering T cells to have artificial chimeric receptors, gene modified TCR therapy uses genetic modification to create T cells that contain a specific T cell receptor. Gene modified TCRs can recognise antigens that are present on the inside of cancer cells (and which are presented on the cell surface by the major histocompatibility complex (MHC)). In contrast, CAR-T cells can only recognise antigens that are expressed on the cell surface.
There are many researchers and companies exploring gene modified TCR therapy globally, including Kite Pharma, Adaptimmune, Cell Medica and University College London. In a recent development (May 2018), Bluebird Bio and Medigene announced an expansion to their ongoing collaboration in this area, which could take the value of the potential milestone payments paid to Medigene to more than $1.5 billion.
Many groups are also using CARs in immune cells other than T cells. One such therapy that is being investigated uses natural killer (NK) cells. NK cells are a type of white blood cell in our innate immune system that are usually involved in killing cells that have become infected with viruses, whereas the T cells used in CAR-T therapy work by recognising specific antigens.
CAR-NK therapy aims to genetically engineer NK cells to contain CARs that target specific antigens in a similar way to CAR-T. CAR-NK therapy is one part of a broader category of NK therapy and it is hoped that it can avoid some of the side effects of T-cell based therapies, such as cytokine storm and graft vs. host disease.
Companies working in this area include NantKwest and Fate Therapeutics.
Regulatory T cells (Tregs) are a subset of T cells that regulate other cells in the immune system. They prevent other immune cells from attacking the body’s own tissues and defects in Tregs result in excessive and harmful immune responses.
The idea behind CAR-Treg therapy is to treat patients who suffer from autoimmune and chronic inflammatory diseases. CAR-Tregs are directed to inflamed areas of the body in order to suppress the harmful immune response. This is achieved by engineering Tregs to express CARs that recognise antigens that are present in these particular areas of the body.
French company TxCell has a number of Treg therapy programmes in the pipeline, including a CAR-Treg-based cellular immunotherapy to prevent organ transplant rejection. In May 2018 it announced a deal with Lonza Pharma for the manufacture of its CAR-Treg product in preparation for clinical testing.
The therapies outlined above are just a selection of immunotherapies that are currently being investigated. They receive less attention in the press than CAR-T therapy but are being watched with a lot of interest as they progress through clinical development.