Tuberous Sclerosis Complex (TSC), is rare genetic disorder that can lead to the growth of non-cancerous (benign) tumours. TSC most commonly affects the brain, skin, lungs, heart, eyes and kidneys. Individuals are also at risk of developing kidney cancer. It is caused by mutations in the genes TSC1 or TSC2. These genes also affect the same pathway that FLCN, the gene mutated in BHD does. We have previously written a blog post about this link. Therefore, research being done in TSC may be of interest and applicable to BHD, and vice versa. In this blog post, we discuss a recent paper investigating the development of an immunotherapy treatment for TSC. Immunotherapy is a type of treatment used in cancer that helps your immune system fight the cancer cells.
Tumours that develop in TSC are a result of the loss of both copies of TSC1 or TSC2. It is possible to identify particular genes or molecules that are only found in tumour cells with a TSC1 or TSC2 mutation. These molecules will not be expressed in “healthy” cells. It may be possible to develop an immunotherapy treatment that can specifically recognise these molecules. This in turn leads to killing of those cancer cells and a reduction in tumour size or even kill the whole tumour itself.
In this paper, Thomas et al., observed overexpression of a molecule called GD3 on the surface of TSC tumour cells. GD3 is normally expressed during brain development but is abnormally expressed in several cancers. GD3 is also known to accelerate tumour growth. They showed that the enhanced expression of GD3 in cells correlated with hyperactivation of mTOR. This suggests that GD3 expression is linked to mTOR activation.
The researchers developed a type of immunotherapy called CAR T cells. As the name suggests, the main component of these are T cells. T cells are a key part of our immune system as they are often the first cells to recognise something is “foreign” in our bodies (e.g. cells infected with a virus). They can then coordinate the immune system to mount a response, or the T cells can directly kill the “foreign” cells instead. The “CAR” in CAR T cells is the bit that enables the T cells to specifically recognise something and kill only those cells. In this instance, the CAR is made to specifically recognise the GD3 molecule and kill the TSC-associated tumour cells.
They tested the GD3 CAR T cells in 2 different mouse models of TSC2-related tumours. In one model, they measured the volume of the tumour over time with GD3 CAR T cell treatment compared to control treatments. They saw that although the tumour volume had increased, the tumours were significantly smaller in those receiving GD3 CAR T cell therapy compared to controls. In the second model, they looked at the number of tumours in the liver and kidney. There was a significant reduction in the number of tumours in the mice that received the GD3 CAR T cell therapy compared to control treatment. They also examined the safety of GD3 CAR T cell therapy in the mice and saw no changes in the tissues they tested.
The work presented in this paper is a promising first step towards treatment for benign tumours in TSC. Although not cancerous, the tumours can cause significant and serious problems. As they can grow anywhere, they can block blood flow or prevent normal functioning of many organs. Developing a treatment for these tumours would therefore be of great benefit. CAR T cells are a very new type of treatment, only approved for certain types of blood cancer. There are currently many clinical trials looking at the safety and effectiveness of CAR T cell therapy in other cancers. It’s a complex procedure and, like many other cancer drugs, can have serious side effects. This approach could have some benefit for the treatment of BHD. However, the tumours associated with BHD are not normally life threatening in the same way as they are in TSC. Regular monitoring of the kidneys minimises the risk of kidney cancer. Tumours are normally removed when they reach 3cm and do not normally affect the function of the kidneys. Therefore, the benefits of this type of treatment must be weighed carefully with the risks. Nevertheless, due to the link with mTOR, it would be interesting to see if GD3 was also upregulated in BHD-associated tumours.