Tumour-infiltrating lymphocyte (TIL) Therapy

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Tumour-infiltrating lymphocyte (TIL) Therapy

What is a Tumour-infiltrating lymphocyte (TIL) and why are they being researched?

Lymphocytes, or white blood cells, are an important part of the immune system that helps the body fight off infections or recognise and attack cancer cells.

Lymphocytes, made up of various T cells and B cells, go around the body as a natural defence system trying to find cells that shouldn’t be there, attacking and killing them.

As a melanoma grows, some T-cells can recognise that the melanoma cells are abnormal, and they move from the blood stream to inside the melanoma. These are the tumour-infiltrating lymphocytes, or TILs and they will recognise and try to kill the melanoma cells.

However, sometimes melanoma cells can stop TILs from attacking and killing them by quickly changing the targets that the TILs recognise or by giving off signals that can weaken the immune system’s response. Therefore, researchers have been looking at how to make the TILs more effective at fighting melanoma.

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Understanding TIL Therapy 

To support the information on this page, we have worked with Dr. Elaine Vickers to create a video which explains how TIL (Tumour-infiltrating lymphocyte) Therapy works, who TIL Therapy is for and its use in the treatment of melanoma.

How can TILs be used to treat melanoma?

TIL therapy is where TILs are taken directly from the patient’s melanoma itself as they already recognise many targets on the melanoma cells. This makes the TILs very useful in treating melanoma because they can already identify it by themselves without having to be altered.

To effectively use TILs to treat melanoma researchers can help them to overcome the way that the melanoma cells can hide from the immune system, which allow it to grow and multiply. Because it uses the immune system, TIL therapy is a type of immunotherapy, and it can also be referred to as personalised cancer treatment.

Researchers currently think this can be done in two ways:

  1. By growing the TILs to very large numbers so that the patient’s body has a much larger army of immune cells that are already trained to recognise and attack that patient’s specific melanoma.
  2. By engineering the TILs to have certain characteristics which improve their ability to target and attack the patient’s specific melanoma (cNeT therapy)

What is the treatment process for TIL therapy?

TILs are isolated from a patient’s own melanoma. Each patient will be assessed to check that doctors can access the melanoma tissue in their body, which in a small number of cases may not be possible. A small part of the melanoma is removed by a minor surgical operation, and this tiny part of the melanoma is broken down into smaller parts in a laboratory.  Specific chemicals are added to encourage the TILs to grow in large numbers, which can take about a month. However, researchers are working on being able to speed up this process to be able to get treatment to patients more quickly.

TIL therapy is an intense treatment, and all patients will be admitted to hospital before treatment starts and will be an inpatient for about 2 weeks. Before receiving the TILs back into their body, the patient will receive treatment with high dose chemotherapy infusions (i.e. through a vein in their arm) over a few days. This is to reduce the number of immune cells in the blood and make room for the new TILs that will be given to them to fight the melanoma.

TILs diagram

The billions of TILs that have been grown in the laboratory will be given back to the same patient by giving an infusion into a vein (i.e. in the arm). The high numbers of TILs circulating in the patient’s body are thought to help their immune system fight the melanoma more effectively, as there will be a higher number of TILs that are available to find, attack and kill the melanoma cells.

This method is known as ‘autologous’, which means that the TILs are given back as treatment to the same patient from which the melanoma cells were originally taken.

TIL therapy is a one-time treatment. After receiving the infusion of TILs the patient will receive some immune-modulating treatment called IL-2 as an infusion (i.e.into a vein in the arm) for a number of days. This treatment is to help stimulate the immune system and the TIL activity in the body.

For the duration of their stay doctors will monitor patients for any side effects or reactions to the therapy at each stage of the treatment process to ensure that they are well before they can go home.

What are the possible side effects of TIL therapy?

Most side effects that have been seen with TIL therapy come from the chemotherapy or the IL-2 treatments, which doctors are used to managing. Patients will be given some medicines to try to prevent more common side effects such as nausea and vomiting, or diarrhoea. Other possible side effects of high-dose chemotherapy and IL-2 can include tiredness, hair loss, bruising and bleeding, fevers or chills, skin rash, mouth ulcers, dizziness, confusion, low blood pressure or increased risk of catching infections.

Side effects relating to the TIL infusion are less common, but patients may develop a reaction including shortness of breath, chills, and fever shortly after the infusion of TILs; this is usually very short-lived and can be treated quickly. Other rare side effects from TILs can develop much later and may be due to stimulation of the immune system.

drip into patients arm

Clonal Neoantigens-reactive T-cell (cNeT) Therapy

What are clonal neoantigens?

Clonal neoantigens are proteins on the surface of a specific patient’s melanoma cells that can make it harder for their immune system to kill the melanoma. Clonal neoantigens can constantly change (mutate) which makes it harder to target and kill them with a generalised treatment.

What are Clonal Neoantigens-reactive T-cells (cNeT)?

CNeT are specific T-cells that are shown to have activity against the clonal neoantigens on the surface of melanoma cells. Researchers have recently discovered that cNeT can be identified from the TILs that have been removed from a patient’s melanoma.

What is the treatment process for cNeT therapy?

After TILs have been grown to large numbers, and before they are introduced back into the body, researchers have found a way of testing in the laboratory to see if they have any action against the specific clonal neoantigens that the melanoma has. The cells that have this specific action are known as clonal neoantigens-reactive T-cells (cNeT) and they can be separated from the other TILs to make the therapy very highly specific to that patient’s melanoma. These extracted cNeT will be combined with a specific chemical to help them grow, resulting in billions of cNeT. These are then given back to that same patient through an infusion into the vein. The patient will follow the same treatment process before and after the cNeT infusion, as with the TIL therapy infusion.

What is the difference between cNeT and TIL therapy?

CNeT are thought to be more specific and therefore more active against melanoma than the conventional TIL therapy, as they specifically target the clonal neoantigens that are known to be on the surface of that patient’s melanoma cells. This makes the treatment more personalised towards the patient’s own melanoma because it uses the cNeT to find and kill the specific melanoma cells from which they were produced.

CNeT therapy is in the very early stages of research, and so researchers around the world still use both cNeT and TIL therapies in clinical trials to be able to gather enough evidence to prove how effective they both are against melanoma.

TIL and cNeT therapy are one-off treatments, but very intense. As well as looking at how effective these treatments are at treating melanoma, doctors are still studying how well patients cope with the therapy and what side effects they may experience during the whole treatment process.

There are currently some early phase trials in the UK looking at TILs and cNet therapy. You can have a look at the ones that are open to recruitment now on our Melanoma TrialFinder.


Resources used to create this page:

Qin SS, Melucci AD, Chacon AC, Prieto PA.  2021; 10(4):808. https://doi.org/10.3390/cells10040808

Rohaan, M.W., van den Berg, J.H., Kvistborg, P. et al. Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. j. immunotherapy cancer 6, 102 (2018). https://doi.org/10.1186/s40425-018-0391-1

Rohaan, M.W., Borch, T.H., van den Berg, J.H. N Engl J Med 2022; 387:2113-2125 https://DOI.org/10.1056/NEJMoa2210233