Immunotherapy is not chemotherapy. In the 1850s German doctors noticed that some cancers shrank if they became infected, and this led to the idea that the body’s own defences, the immune system, could be used to help fight cancer. However, it wasn’t until the 1980s that scientists at the Christie Hospital in Manchester, England proved that the protein interferon alpha (IFN-α) could cause tumours in low-grade lymphoma patients to shrink. This led to further research and IFN-α is now used in several types of haematological malignancies and cancers, including renal cancer. Interleukin-2 (IL-2 or aldesleukin) is also used for the treatment of renal cancer.
Both IFN-α and IL-2 are cytokines – specialised proteins occurring naturally in the body, manufactured by the white blood cells called T-cells. Cytokines are normally produced in the body in response to infection and allow infected cells to ‘warn’ neighbouring cells of the threat and stimulate their defences. These naturally occurring proteins can be made in the laboratory, and injected or infused intravenously to treat renal cancer. It is not completely understood how they work, but they can work in several ways:
- Interfering with the way cancer cells grow and multiply.
- Stimulating the immune system and encouraging killer T-cells and other cells to attack cancer cells.
- Encouraging cancer cells to produce chemicals that attract immune system cells to them.
Interferon Alpha (IntronA®, Roferon-A®)
IFN-α is given as a subcutaneous injection, usually with a pre-filled syringe or an injection-pen mechanism to allow the patient to be taught to self-administer. Interferon is a protein the body makes in very small amounts. It can also be made outside the body and used as a drug.
Interferon is given to stimulate the body’s immune system to fight some types of cancer. The immune system is the body’s defence against infection and disease.
Interferon may:
- slow down or stop the cancer cells dividing
- reduce the ability of the cancer cells to protect themselves from the immune system
- strengthen the immune system
(Macmillan, 2017)
Side Effects
- Flu-like symptoms, such as fever, chills, headache, aching muscles and joints.
- Fatigue
- Nausea and vomiting
- Diarrhea
- Loss of appetite
- Headache
- Haematological disturbances, such as anaemia, thrombocytopaenia and neutropaenia
- Rarely, IFN-α can also cause skin rashes, depression, hair thinning, changes in liver enzymes and heart problems.
Interleukin-2 ( Aldesleukin, Proleukin®)
High dose IL-2 has very toxic side effects and patients having intravenous treatment with IL-2 have to be admitted to a high dependency unit bed. The overall response rate in patients receiving a high-dose IL-2 bolus is 15-23%; however, less than 5% of patients receiving high dose IL-2 derive long-term benefit at the expense of significant toxicity. Of these patients, a durable benefit is seen in two thirds of complete responders. Overall, no survival difference is seen between high dose IL-2 and other immunotherapies, such as IFN-α.
IL-2 is usually given as a subcutaneous injection, daily for 5 days then 2 days rest for 4 weeks, then a week off. These ‘cycles’ of treatment can be repeated as necessary.
IL-2 may be used in combination with IFN-α and 5-fluorouracil (5FU, a chemotherapy). This is called the Atzpodien regime, but is quite toxic and no longer used widely.
Side Effects
- Flu-like symptoms, such as fever, chills, headache, aching muscles and joints.
- Fatigue
- Nausea and vomiting
- Diarrhoea
- Loss of appetite
- Skin rash
- ‘Vascular leak syndrome’ – this usually only happens when having IL-2 intravenously. Fluid leaks out of the small blood vessels and can cause low blood pressure, difficulty breathing, weight gain, oedema of face, ankles and legs, and low urine output. Steroids can help prevent this.
- Haematological disturbances such as anaemia, thrombocytopaenia and neutropenia
- Heart problems
- Kidney changes
- Rarely, IL-2 can also cause hair thinning, confusion and depression.
As the risks with IL-2 are so great, and it only benefits a small percentage of people, it is not widely used and tends to be used in a few specialist centres. It is only administered to patients who are otherwise healthy and well enough to withstand the severe side effects. IL-2, therefore, still has a place in the treatment of a small minority of patients where it offers the hope of durable remission.
The future for immunotherapy
Immunotherapies, such as interleukin-2 and interferon-alpha, used to be the main treatment for advanced renal cancer. However, their use has been superseded by targeted therapies, which are more effective at controlling the cancer and have less severe side effects. In the UK, cytokines are now used in less than 10% of patients with advanced renal cancer.
Monoclonal antibodies
Nivolumab (Opdivo®) was recommended by NICE as a second-line treatment of advanced kidney cancer in November 2016. Nivolumab acts to work with the patient’s own immune system. Nivolumab blocks PD-1 receptors on immune cells and therefore reduces the dampening down effect of PD-1 on the immune system, so more immune cells are active to kill cancer cells.
Nivolumab is a monoclonal antibody, which recognises and blocks a protein receptor on immune T-cells called PD-1. Tumour cells can produce PD-L1 which activates the PD-1 receptors, causing the immune cell to be less active. Nivolumab works as a checkpoint inhibitor, blocking the signal that would have prevented activated immune cells from attacking the cancer, thus allowing the immune system to clear the cancer.
Nivolumab is administered through a drip into a vein every two weeks for about an hour. Generally, nivolumab is well tolerated. However, the most common side-effects associated with nivolumab are immune-mediated inflammatory conditions; such as inflammation of the colon, lungs, liver, kidney and thyroid.
Side Effects
- Tiredness
- Diarrhoea
- Nausea
- Coughing
- Skin reactions
New combinations
Nivolumab with ipilimumab (Yervoy) was recommended for use within the NHS in 2022 as an option for adults with untreated and advanced renal cell carcinoma that is intermediate- or poor-risk, and Avelumab (Bavencio) with Axitinib (Inlyta) was recommended in 2020 as an option for adults with untreated and advanced renal cell carcinoma for use within the cancer drugs fund.[1]
Pembrolizumab (Keytruda) and Axitinib combination therapy has been accepted by NHS Scotland for first-line treatment of advanced kidney cancer in 2020, but is still not available in the rest of the UK, it is currently under review by NICE [2] Also the combination therapy of Cabozantanib and Nivolumab has been made available for patients as a first line treatment in Scotland from October 2021.[3]
Other varying combinations of different monoclonal antibodies and targeted therapies are likely to be seen in up and coming clinical trials in the near future.
- NICE first line treatments
- Pembrolizumab and Axitinib
https://www.kcsn.org.uk/pembrolizumab-plus-axitinib-combination-accepted-by-nhs-scotland-for-first-line-treatment-of-advanced-kidney-cancer/ September 7, 2020 (KSCN 2020)
- Nivolumab and Cabozantanib https://pharmaphorum.com/news/scotland-backs-cabometyx-combo-for-kidney-cancer-amid-stalled-nice-review/ October 2021