An example of targeted immunotherapy

A DEFINITION

The goal of immunotherapy is to stimulate the immune system so that it can seek out and eliminate cancer cells on its own.

Immunotherapy is a promising therapy for many patients and a wide array of cancers.

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WHAT IS THE IMMUNE SYSTEM?

The immune system plays a key role in our organism’s defence. Many organs, tissues, cells and proteins are involved.

As an illustration, when an infectious agent enters our body (virus, fungus, bacteria or parasite), the immune system recognises it as a foreign body.

immune response

Like an army sending its soldiers, tanks and drones to the battlefield to fight off the enemy, the immune system sets off myriads of reactions to fight off an invader. The immune response is an extremely intricate and complex molecular process.

 

In particular, the immune system sends specialized cells known as T lymphocytes to the battlefield, or proteins such as antibodies (produced by cells known as B lymphocytes).

 

The whole system is fine-tuned by a series of ‘regulator’ cells.

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THE IMMUNE SYSTEM AND CANCER

THE IMMUNE SYSTEM CAN ELIMINATE CANCER CELLS

YES, it can! Our immune system plays a key role in the fight against cancer, because it can recognise and eliminate cancer cells.

 

How can it do this? Since cancer cells originate from an initial normal cell…? Because cancer cells accumulate so many molecular anomalies that they end up being very different to a normal cell and are finally recognised as ‘abnormal’ by the immune system.

BUT THERE’S A PROBLEM…

As they accumulate molecular anomalies, certain cancer cells acquire the means to shun the immune system by becoming ‘invisible’ to it!

 

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IMMUNOTHERAPY, HOW IT WORKS

The principle of immunotherapy is to set off and/or stimulate an immune response specifically targeted at cancer cells.

Several drugs used in immunotherapy target the actual strategies cancer cells have acquired to shun the immune system…

The tables are turned!

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AN EXAMPLE: IMMUNOTHERAPY AND THE IMMUNE CHECKPOINT

TOLERATING ‘SELF’

Under normal circumstances, our immune system does not attack what already belongs to us, in other words it does not attack what it senses as ‘self’, such as our cells for instance. This is called immune tolerance.

In some unfortunate cases, our immune system turns against our own body causing diseases, such as rheumatoid polyarthritis or multiple sclerosis. These diseases are called auto-immune diseases.

 

Immune tolerance is therefore limited to a point beyond which our immune system recognises constituents as ‘non self’ and will set out to attack it. This point is called the ‘immune checkpoint’. It is very fine-tuned, and certain auto-immune diseases are avoided thanks to it.

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PD1 AND PD-L1: TIGHT COLLABORATION

PD1 and PD-L1 are two proteins involved in ensuring the immune checkpoint.

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STANDBY MODE...

PD1 is expressed on the surface of T lymphocytes.

PD-L1 is only expressed on the surface of certain cells that regulate the immune system.

These two proteins collaborate in unison to regulate the immune system, notably by slowing it down and even putting it into standby mode.

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WHEN EVERYTHING WORKS OUT...

The immune system recognises cancer cells as ‘abnormal’. Consequently, it gets T lymphocytes to launch an attack.

Cancer cells appear on a regular basis in our organism. Fortunately, they are usually eliminated by our immune system.

 

 

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WHEN STANDBY MODE IS HACKED...

PD-L1 is usually only expressed on the surface of certain cells that regulate the immune system.

However, in about 20 to 50% of cancers, PD-L1 is equally expressed on the surface of cancer cells!

What does this mean? T lymphocytes will recognise the cancer cells as ‘abnormal’ cells. However, because of the presence of PD-L1 on the surface of the cancer cells and of the interaction between PD1 and PD-L1, the T lymphocytes are checked and put into standby mode.

Cancer cells that express PD-L1 on their surface are therefore able to shun the immune system!

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HOW IS THIS POSSIBLE?

Cancer cells accumulate molecular anomalies, and whole parts of chromosomes are sometimes duplicated. When this happens, certain genes are found in multiple copies and their expression becomes anarchic.

This is what happens to PD-L1. The PD-L1 gene is exclusively expressed in certain cells that belong to the immune system. Following the presence of multiple copies of its gene in cancer cells, the PD-L1 protein ends up by being expressed on their surface. As a result, the cancer cells are not detected by the immune system.

 

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CAUSE FOR HOPE

One approach used in immunotherapy consists in preventing PD1 from interacting with PD-L1. In this way, the normal immune response is restored and the cancer cells are eliminated. This strategy earned James P. Allison and Tasuku Honjo the 2018 Nobel Prize in medicine.

Since 2015, immunotherapies that use molecules – drugs – to target PD1 and PD-L1 have become common. These particular drugs are known as ‘immune checkpoint inhibitors’ or ICIs. As an illustration, the drug nivomulab is an antibody that targets protein PD1. When nivomulab is bound to PD-1, PD1 and PD-L1 cannot interact anymore.

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PERSONALIZED TREATMENT

Treatments that target PD1 or PD-L1 are only prescribed if the PD-L1 protein is present on the patient’s cancer cells.

DETECTING THE PD-L1 PROTEIN

PD-L1 is detected by using techniques in immunohistochemistry. The tumour’s cells are studied under the microscope in the presence of specific PD-L1 antibodies to which are bound fluorophores or chromophores. In this way, if PD-L1 is present, the cells are ‘marked’ by the ‘coloured’ antibodies and can easily be distinguished.

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IMMUNOTHERAPY: ALTERNATIVE TARGETS

PROTEINS CTLA-4 AND IDO1

Besides PD1 and PD-L1, other proteins are also involved in regulating the immune response and can equally be taken as targets in immunotherapy treatments.

Like PD1 and PD-L1, a protein known as CTLA-4 can also slow down the immune response. In particular, an antibody known as ipilimumab targets CTLA-4 and is used to treat certain cancers also by stimulating the immune system.

When overexpressed by cancer cells, yet another protein – known as IDO1 – induces a toxic environment for T lymphocytes. Drugs that inhibit IDO1 restore the immune response and may well also partially strengthen the effectiveness of other immunotherapies.

 

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Other types of immunotherapy, all of which boost one way or another the immune system, do not necessarily target anomalies or features that are present in cancer cells.

As an illustration, the T lymphocytes of a cancer patient can be genetically modified in a laboratory and then reimplanted in his/her body so that they destroy cancer cells more effectively.

All these ongoing novel immunotherapies are a genuine cause for hope!

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