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What is immunotherapy?
Immunotherapy refers to treatment that harnesses a person’s own immune system to fight cancer. Our immune system functions as the body’s defence mechanism against infections and other diseases, including cancer.
Cancer cells have molecules on their surface (called antigens) that can trigger the immune system to find and destroy them, but some cancer cells may evade the immune system’s surveillance in ways such as:
- losing the antigen expression and presentation on their cell surface.
- releasing chemicals to make the environment around cancer cells less conducive to immune cell attack.
- upregulating expression of immune checkpoint molecules to ‘turn off’ the immune response.
Immunotherapy boosts the immune system or helps the immune system to find and destroy cancer cells. There has been tremendous progress in its use over the last few decades and it has become the fourth pillar in cancer treatment after surgery, chemotherapy, and radiotherapy.
Immune checkpoint inhibitors
The immune system normally stops T cells (a type of immune system cell) from attacking normal cells in the body by using proteins called immune checkpoints. Immune checkpoints slow down or put the brakes on immune system responses.
Some cancer cells can mimic the behaviour of healthy cells by producing these checkpoints on their cell surface. By doing this, these cells trick the immune system by sending the ‘OFF’ signals to stop the immune attack. This allows cancer cells to camouflage from the immune system and continue growing.
There are various immune checkpoints in our normal immune system. Doctors have successfully used monoclonal antibodies against some of these immune checkpoints to block the false ‘OFF’ signals and allow the immune system to remain in the ‘ON’ state to efficiently find and destroy the cancer cells.
The first immune checkpoint inhibitor – targeting an immune checkpoint known as CTLA-4 – was approved in 2011 for the treatment of melanoma (a type of skin cancer). This was quickly followed by the development of other antibodies that target checkpoints such as PD-1 and PDL-1.
Currently, various checkpoint inhibitors have been approved as standard treatments for many cancer types. The approvals are not limited to advanced cancers but have extended to some early-stage cancers at high risk of relapse after surgery.
Immune checkpoint inhibitors can be used alone or in combination with other drugs such as chemotherapy or targeted therapy to further improve the clinical outcome, with a very durable response in some patients.
Moving forward, new antibodies against other immune checkpoints are actively being developed with the hope of further enhancing the clinical activity or improving the treatment safety profile.
How are immune checkpoint inhibitors administered?
Immune checkpoint inhibitors are given into a vein (intravenous) as an infusion, typically over 1-2 hours. Treatment is usually delivered in an outpatient clinic.
Immune checkpoint inhibitors have a relatively long duration of action that allows your care team to deliver a dose every 2 to 12 weeks depending on the drug and dosage.
The duration of treatment is usually limited to 1 year for patients with early-stage cancer and 2 years or more for most patients with advanced cancer.
Can immune checkpoint inhibitors offer a cure for cancer?
In selected cases with a good response to treatment, patients can remain in an extended period of remission long after the last dose of treatment. These observations prompted doctors and patients to consider if their cancers have been cured. A longer follow-up will provide further information on this possibility.
However, it is important to understand that checkpoint inhibitors are not effective across all cancer types. Even within the same cancer type (e.g non-small cell lung cancer), there are only certain groups of patients who are likely to benefit from immune checkpoint inhibitors.
As yet, there is no perfect biomarker of response to immune checkpoint inhibitors. This is because the interaction between the immune system and cancers is much more complex than the ‘ON’ and ‘OFF’ states that the immune checkpoint inhibitors are trying to manipulate.
Which cancers are treated with immune checkpoint inhibitors?
Immune checkpoint inhibitors have been successfully used on many different cancer types. Today, they are often used in combination with other therapies to improve treatment outcomes. There is ongoing research and development to expand the scope of immunotherapy for cancers.
Examples of cancers that benefit from immune checkpoint inhibitors include:
- Non-small cell lung cancer
- Small cell lung cancer
- Kidney cancer
- Head and neck cancer
- Bladder cancer
- Breast cancer
- Liver cancer
- Oesophageal cancer
- Stomach cancer
- Cancers with genetic features of mismatch repair deficiency
- Lymphoma and many more
It is important to understand that not all cancer patients are eligible for immunotherapy, and not all cancer can be treated with immunotherapy. Be sure to discuss with your doctor whether the treatment is suitable for you.
Immunotherapy Side Effects
What are the possible side effects of immune checkpoint inhibitors?
Immune checkpoint inhibitors are generally well tolerated by most patients, especially when used alone. However, there are possible side effects to monitor for.
By blocking checkpoint proteins, these drugs remove the ‘brakes’ on the activated immune system to target cancer cells. The ‘overactive’ immune response may not be limited to cancer cells alone. Sometimes the immune system responds by attacking other normal parts of the body, which can cause uncommon but serious problems in the lungs, intestines, liver, hormone-making glands, kidneys, nervous system or other organs.
It is very important to report any new side effects such as those listed below to doctors as soon as possible. If serious side effects do occur, treatment may need to be stopped and you may be given high doses of corticosteroids to suppress your immune system.
- Skin rash
- Muscle and joint pain
- Weakness in limbs
Very rarely, you may experience infusion reactions while receiving these medications (given via an infusion). These can include fever, chills, flushing of the face, or wheezing.
It is important to note that the side effects of immunotherapy tend to occur weeks or months after the treatment has started. In some cases, they may only become apparent after treatment has stopped. Your doctor will provide advice on the necessary monitoring during and after treatment.
Other Types of Immunotherapy
Immune checkpoint inhibitors are the main types of cancer immunotherapy in clinical practice currently. There are various types of other treatments that work on the immune system to treat cancer. Examples include:
- Chimeric Antigen Receptor (CAR) T-cell Therapy modifies millions of T cells collected from patients by adding the chimeric antigen receptors (CARs) on their surface. These receptors recognize a specific antigen (protein) found in the specific cancer being treated. After the modification, the T cells are then infused back to the patients where they multiply, attack and destroy the cancer cells. Examples include tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) for the treatment of relapsed or refractory (not responsive to treatment) diffuse large cell lymphoma (DLBCL).
- Monoclonal antibodies that target specific proteins expressed on cancer cells. For example, Rituximab works against CD20 and trastuzumab works against HER2. These antibodies mark out the cancer cells for immune cells to attack.
- Conjugated monoclonal antibodies that have potent chemotherapy attached to them. The potent chemotherapy is released when the conjugated monoclonal antibodies bind to cancer cells that express abnormal proteins. Examples include trastuzumab deruxtecan (antibody against HER2) and enfortumab vedotin (antibody against nectin-4 – commonly expressed in bladder cancer).
- Non-specific immunotherapy uses cytokines (chemicals) or other substances to trigger the immune system to fight cancer. Interferon and Interleukin are examples of cytokines that were used to treat kidney cancer and melanoma before the discovery of effective checkpoint inhibitors which have replaced their role. Bacillus Calmette-Guerin (BCG) is a type of modified bacteria that is still being used for very early superficial bladder cancer by triggering an immune response when instilled into the bladder.
- Immunomodulating drugs that boost the immune system such as lenalidomide are used in multiple myeloma and some lymphoma.