There are lots of exciting new ideas for fighting cancer. One idea is to genetically engineer T cells against cancer – but how exactly do we go about programming this ‘search and destroy’ activity?
What are T Cells?
Cytotoxic T cells represent a key part of the ‘cellular’ arm of the body’s adaptive immune system, which serves to recognise and kill diseased cells such as those with viral infections. This is a very specific response, in that once the cells are generated they only respond to the exact target against which they were designed.
Why use T Cells Against Cancer?
T cells use their T cell receptor (TCR) to recognise specific molecular markers on cells called antigens. The idea is that if we can make T cells that recognise cancer cells, we’d have a very effective method of specifically targeting and killing cancer cells. This would be a big advantage over chemo- and radiotherapies which have damaging effects on lots of cell types, including our healthy cells, leading to widespread side effects.
Why do T cells need to be Genetically Engineered in order to Target Cancer Cells?
Firstly, the T cells need to be able to recognise the cancer cells. This means that their TCRs need to be specific for markers on the cancer cells, known as tumour-associated antigens (TAAs). Tumour cells may also have mechanisms to avoid being targeted by the immune system. These include down-regulating expression of TAAs in order to avoid detection by T cells, and creating an immunosuppressive microenvironment around the tumour to dampen any responses against it. T cells must be engineered to overcome these evasion strategies.
Localisation of T cells to the tumour site, and encouraging long-lived T cell responses against the cancer cells, are also factors that help determine the effectiveness of the response. These are therefore targets for further genetic engineering.
What Genetic Modifications can be made to Help T Cells Target Cancer?
To generate T cells with TCRs that recognise the cancer cells (rather than any other cells), several approaches can be taken. These include (i) using or modifying existing ‘natural’ TCRs from patients with immune responses against cancer, (ii) using TCRs from in vivo (animal) models such as mice or (iii) engineering chimeric antigen receptors (CARs), which are essentially man-made TCRs. Unfortunately, our abilities to isolate these cancer-specific T cells from humans are limited, and the effectiveness of using them has proven poorer than anticipated, and so there has been an increasing focus on developing and using CARs when designing anti-cancer T cell therapies.
However, fine-tuning this targeting system on T cells isn’t the only factor to consider. T cells also require co-activating signals to fully activate their killing mechanisms, and therefore these signals are also needed for successful therapy. The development of second and third generation CARs, which are made to provide their own co-stimulatory signals through genetic engineering of signalling domains into their CARs, have made some headway in addressing this problem.
As we mentioned before, localisation of T cells to the site of the tumour is essential. Normally, T cell localisation is mediated by a complex series of interactions of receptors on the T cells and chemical signals called chemokines. However, sometimes the T cells are not able to receive these signals because they are not expressing the necessary chemokine receptors. Engineering these receptors, so that they’re constitutively (always) expressed on the surface of anti-cancer T cells, is one way to aid localisation.
Persistence of the T cell response is key to tackling cancer effectively with this method. Often T cell responses do not persist and therefore lose their effectiveness because our normal homeostatic mechanisms cause the active T cells to apoptose (die). To avoid this, T cell therapies have been engineered so that they don’t express their usual ‘death receptors’ – these are receptors that cause the cell to die once activated. Linking repressive signalling pathways to stimulatory pathways in the cell can also lead to increased persistence of T cell responses.
So there’s a whistle-stop tour of how our own immune system can be used in the fight against cancer – and many of these therapies are now showing promise in trials! Unfortunately, they are currently VERY expensive, and the therapies have to be VERY specific for the patient, both of which are obstacles that must be overcome before therapy can be rolled out on a larger scale.
Kershaw MH, Westwood JA, & Darcy PK (2013). Gene-engineered T cells for cancer therapy. Nature reviews. Cancer, 13 (8), 525-41 PMID: 23880905