Our researchers are working on an innovative form of immunotherapy that harnesses the body’s own immune cells to kill cancer cells.

Called CAR-T cell therapy, this treatment involves isolating a patient’s immune cells, engineering them to become ‘super killer cells’ and then reinfusing them into the patient to fight their cancer.

This technique has been successfully used to treat blood cancers but has had mixed results in solid tumours.

Our researchers are studying the biological factors contributing to the success and side effects of CAR-T cells. This work will help inform a better design and safer delivery methods.

Brain cancer is a particular focus for this work, with our researchers are aiming to find an optimum design for CAR-T cell therapy that can kill brain tumour cells with limited side effects.

Immune checkpoints are the brakes of the immune system, allowing immune responses to be switched off after a threat – such as a virus infection – is over. Without these brakes, uncontrolled immune responses can cause inflammatory tissue damage and autoimmune disease.

However, some cancer cells take advantage of these brakes, using them to switch off immune cells that would otherwise destroy the tumours.

Immune checkpoint inhibitors release the brakes, enabling immune cells to attack tumours.

Some of the most exciting new cancer therapies are known as anti-PD1 and anti-CTLA4 immunotherapies. Our researchers are studying these immunotherapies in several preclinical models of cancer, including lung, stomach and breast cancer.

This research could help to identify patients who may benefit from these immunotherapies and lead to future clinical trials aimed at improving patient outcomes.

Natural killer cells are part of the body’s first line of defence against infections and cancer.

Our researchers are studying how natural killer cells fight cancer, with the aim of harnessing these cells to specifically detect and destroy the disease.

They have discovered a protein – called CIS – that acts as a brake to dampen natural killer cell activity. Blocking CIS increases anti-tumour activity and reduces melanoma growth in preclinical models.

Our researchers are now partnering with a drug company to develop inhibitors of CIS that may ultimately help patients fight cancer with their own immune system.

Immunotherapy can be used to dampen down harmful immune responses, for example in:

• coeliac disease, which is caused by an inappropriate immune reaction to the gluten protein found in wheat, rye and barley
• type 1 diabetes, which is caused by the immune system wrongly attacking healthy cells in the pancreas

Our researchers are performing a clinical trial pairing the diabetes immunotherapy with an immunosuppressive agent to test if the combination will slow the progression of type 1 diabetes.

Cells can die because they are damaged, but most cells die by killing themselves.

There are several distinct ways in which a cell can die. Some occur by an organised, ‘programmed’ process. Some cell death processes leave no trace of the dead cell, whereas others activate the immune system with substances from the dead cell.

Apoptosis: is a form of cell death that prevents immune activation. Apoptotic cells have a particular microscopic appearance. The cell activates proteins called caspases that are normally dormant. These caspases dismantle the cell from within. The apoptotic cell breaks into small packages that can be engulfed by other cells. This prevents the cell contents leaking out of the dying cell and allows the components to be recycled.

Necrosis: occurs when a cell dies due to lack of a blood supply, or due to a toxin. The cells’ contents can leak out and damage neighbouring cells, and may also trigger inflammation.

Necroptosis: is similar in appearance to necrosis, in that the dying cell’s contents can leak out. However, like apoptosis, necroptosis is a programmed suicide process triggered by specific proteins in the dying cell.

Pyroptosis: is a form of cell death that occurs in some cells infected with certain viruses or bacteria. A cell dying by pyroptosis releases molecules, called cytokines, that alert neighbouring cells to the infection. This triggers inflammation, a protective response that restricts the spread of the viruses and bacteria.

Many proteins have been discovered that control whether a cell dies by the processes of apoptosis, necroptosis or pyroptosis.

Some key cell death control proteins include:

• Caspases: these enzymes are switched on in apoptotic cells, and digest other proteins to bring about cell death. Some caspases have roles in processes other than cell death.
• Bcl-2 family proteins: these proteins interact with each other to determine whether a cell undergoes apoptosis or stays alive. Some Bcl-2 family proteins promote survival, and block apoptosis. Others are ‘pro-death’, and trigger apoptosis.
• Death receptors: these are proteins on the surface of the cell. When they are bound by certain cytokines (hormone-like signalling proteins), they cause changes in the cell that can lead to cell death.
• RIP kinases: two proteins called ‘RIP1 kinase’ and ‘RIP3 kinase’ trigger necroptosis.
• IAPs: or ‘inhibitor of apoptosis proteins’ can prevent cell death. They can do this by blocking several cell death proteins including caspases and RIP1 kinase.
• SMAC/Diablo: is an inhibitor of IAPs. In healthy cells, SMAC is stored away from IAPs, in parts of the cell called mitochondria. When cell death is triggered, SMAC can leak out and block IAPs function. Thus, the release of SMAC out of mitochondria can promote cell death.

Many diseases are associated with abnormal cell death. Some examples of this are:

• cancer: cancer cells often resist cell death, even after anti-cancer treatment.
• autoimmunity e.g. Lupus, type 1 diabetes: immune cells that attack the body’s own tissues normally die. If this cell death does not occur it can cause diseases such as lupus or type 1 diabetes.
• viral infection: viruses need to keep a cell alive in order to reproduce. Cell death can therefore prevent viral replication.
• heart attack: many cells, including those in the heart and brain, trigger their apoptosis machinery when they lose their blood supply.

Understanding how proteins such as the Bcl-2 family control cell death has led to the development of new drugs to block their function. These have the potential to cause the death of cancer cells, or the immune cells that cause autoimmune disease.

One set of drugs, called ‘BH3 mimetics’ trigger apoptotic cell death. They do so by preventing the action of ‘pro-survival’ Bcl-2 family proteins. Unless blocked, these pro-survival proteins help cancer cells stay alive, even after anti-cancer treatments such as chemotherapy.

Clinical trials are underway to determine whether BH3 mimetics can be used to treat certain cancers. BH3-mimetics might also potentially help treat autoimmune diseases by killing disease-causing white blood cells.

SMAC-mimetics are agents that, like the SMAC protein, enhance cell death. They do this by stopping IAPs from blocking cell death. They might also be able to help cells die so that chronic viral infections can be cleared.

There is also considerable interest in agents that can prevent cell death. These could have applications for treating conditions in which there is unwanted cell death, such as stroke, heart attack or neurodegenerative disorders.

Cancer cells have features that distinguish them from normal cells.

Many processes that occur in cancer cells are also seen in normal cells. The difference between cancer cells and normal cells is how these processes are controlled. It is the improper regulation of cell division, cell death and blood vessel growth that drives cancer formation.

The features of cancer cells are caused by abnormalities in specific proteins. These abnormalities can be either an excess amount of, or a lack of, a particular protein. In some cancers, the way a protein functions, called its activity, can be changed. This is often caused by changes, called mutations, to the gene giving instructions for making the protein.

Cancer is treated either by halting the growth of the cancer cells, by killing the cancer cells within the body, or by surgically removing them. If all the cells in a cancer are not completely killed or removed, there is a risk that the cancer will ‘recur’ or ‘relapse’.

Understanding how changes in genes and proteins give cells cancer-like features is leading to new treatments for cancer. Potential new anti-cancer agents are being developed that block the function of the proteins that allow cancer cell growth.

Related information:

• Medicinal chemistry: how basic cancer research can be used to develop potential new anti-cancer treatments.
• Immunotherapy: our researchers are working on an innovative form of immunotherapy that harnesses the body’s own immune cells to kill cancer cells.
• Clinical translation: how our cancer discoveries are being translated into better treatments for patients.

Every human cancer has developed because of unique changes to genes and proteins. Even two people’s cancers that have arisen from the same cell type can be very different at a molecular level.

These molecular differences can influence:

• how quickly the cancer grows
• whether, and where the cancer cells spread around the body (metastasise)
• how well the cancer responds to different treatments
• whether the cancer will come back (relapse) after treatment

Our researchers are determining how people with cancer can be matched to the best treatment for their individual disease. You can read more about this on our personalised medicine page.

Personalised medicine is already a part of our healthcare. When a doctor uses family history or past medical events and results to make treatment decisions, it is a type of personalised medicine.

The future of personalised medicine will increasingly involve genomics, the study of information from a patient’s entire genetic sequence. DNA sequencing is becoming faster and more sophisticated. This makes it easier to determine the best treatment based on genetics of the disease and the individual.

Some of the most advanced examples of personalised medicine have been made in improving the diagnosis and treatment of cancer.

Cancer develops when cells accumulate DNA changes (‘genetic mutations’) that make them grow in an uncontrolled manner. As cancers progress they undergo further genetic changes that enhance their spread (metastasis) or make them resistant to anti-cancer treatments.

Personalised medicine, including genetic sequencing of cancer samples, helps clinicians to match a patient with the appropriate treatment.

New medications called targeted therapies are designed to counteract cancer-causing molecules. For example, patients with breast cancers that have abnormally high amounts of a protein called HER2 can be successfully treated with a medication that blocks HER2.

It is hoped that developments made in personalising cancer treatment could also be translated to other complex conditions.