Introduction

Immunotherapy is a type of treatment that can be used for a range of different cancers and it works by boosting the body's immune system to help it recognise and attack cancer cells. The kidneys are two bean-shaped organs located around the middle of the back. They are used as a filtration system by the body to remove waste products and recycle helpful substances around the body. Kidney cancer occurs when abnormal cells in either of the kidneys grow and multiply at an uncontrollable rate, which can lead to encroachment of tissues and structures, and it can spread around the body. Immunotherapy can target these cells more directly, allowing the body to recognise and destroy them better. 

How do the kidneys work?

As mentioned, the kidneys work as a filtration system for the body to remove waste products from the bloodstream. As well as filtering the waste, they also carry out other vital processes:¹

• Control the production of red blood cells 
• Make vitamins that control growth 
• Release hormones to help regulate blood pressure 

The kidneys complete these processes via a small network of tubes called nephrons, which filter the blood.² As the blood passes through these tubes, the glomerulus acts as the filter, allowing smaller molecules, waste and fluids to pass out of the blood vessel into a structure known as the tubule.³ Larger molecules, such as blood cells and minerals, remain in the blood vessels and are sent back around the body. 

A blood vessel runs parallel to the tubule. As the filtered substances flow down the tubule, the blood vessel reabsorbs the water and minerals into the body, whilst the remaining products in the tubule are carried to the bladder as waste to be removed from the body as urine. This is done via small tubes called ureters, which connect each kidney to the bladder. The bladder then removes urine via a tube called the urethra.⁴

Overview of kidney cancer

Kidney cancer is the eighth most common cancer in adults in the UK, and Renal Cell Carcinoma (RCC) accounts for 80% of these cases.⁵ The cancer occurs when abnormal cells multiply uncontrollably; in an RCC case, this cell growth generally begins in the lining of the tubules. Clear cell RCC are the most common form of RCC and are given their name due to the tumours' bubble-like appearance under a microscope.  

Less common types of kidney cancer

Von-Hippel-Lindau disease (VHL) 

VHL disease is a hereditary form of cancer which can cause tumours in the retina (of the eye), the central nervous system and the inner ear. However, it typically first presents as RCC in the kidney.⁶

Papillary renal carcinoma 

Papillary renal carcinoma makes up 15% of RCC and causes tumours in the tubules. There are two types: type 1, which is the more common form and grows slowly, and type 2, which grows faster and is more aggressive.⁶

Urothelial cancer/Transitional cell cancer

Transitional cells are cells that can shape and stretch and make up the lining of structures such as the ureters, bladder and urethra.⁷ This type of cancer begins in these cells, and it is rare. 

Understanding immunotherapy

The immune system has many different mechanisms for recognising and attacking abnormal cells and foreign microorganisms. However, cancer cells can grow when the immune system isn't strong enough to attack them, and they can also use different mechanisms to avoid being detected by the immune system. 

The immune system contains cells, known as T-cells, whose function is to recognise and mediate targeted responses to specific abnormal cells.⁸ The immune system uses these cells as ‘checkpoints’ in the immune system to prevent anything that shouldn't be there from growing and thriving. 

Kidney cancer often uses these checkpoints to hide and go undetected by the immune system. There are proteins on the surface of T-cells that can be directly targeted by immunotherapy to boost the immune response against cancer cells. 

PD-1 Inhibitors

PD-1 inhibitors are drugs that target a type of protein found in T-cells, whose role is normally to prevent cells from attacking other cells in the body. Blocking these proteins boosts the immune response against the cancer cells. This can shrink tumours and slow their growth. 

An example of a PD-1 inhibitor is Nivolumab, which is given every two weeks via IV infusion. It is generally used as a treatment for people with advanced RCC with prior therapy or in combination with another PD-1 inhibitor as a first-line treatment.⁹ It can cause possible side effects such as fatigue, diarrhoea, high blood pressure, skin rash, shortness of breath, and a cough. 

CTLA-4 Inhibitors

CTLA-4 is another immunotherapy drug that can treat kidney cancer but with a different protein target of CTLA-4 found on T cells. An example is Ipilimumab, which is recommended for RCC adult patients whose disease is considered intermediate or poor risk.¹⁰ It is often given in combination with Nivolumab. 

Common side effects of immunotherapy

Checkpoint inhibitors, as mentioned above, can cause the immune system to become overactive, which can lead to inflammation in other parts of the body. This can cause symptoms affecting a range of different areas of the body, including: 

• The skin 
• Thyroid glands 
• Bowels 
• Joints 

Inflammation in these areas can lead to symptoms of:

• Rashes 
• Overactive or underactive thyroid 
• Diarrhoea 
• Pain and swelling in joints. 

More rare symptoms that may occur include problems in: 

• Liver 
• Brain 
• Lung 
• Heart 
• Nerves 
• Other organs 

The treatment landscape of immunotherapy for kidney cancer

Cancer treatment is constantly evolving and changing all the time as advances in science and technology are made. In this section, we will explore the current recommendations for immunotherapy treatment of kidney cancer. 

If kidney cancer is suspected, diagnostic tests to confirm will include imaging and biopsies of the suspected RCC. Once a diagnosis is confirmed, the extent of the cancer is established. This is done by assessing the size and location of the tumour and whether or not it has spread to other parts of the body, known as metastatic cancer. The anatomic involvement of disease defines the tumour stage and is one of the strongest prognostic factors in the clinical outcomes of RCC patients.¹¹

Localised renal cell carcinoma 

If the cancer is identified to be localised, meaning it is only in one area and has not spread throughout the body, then surgical intervention may be a treatment option. Laparoscopic or open surgery can sometimes be performed to remove any cancer cells. 

Non-surgical intervention options may include treatments such as thermal ablation, radiofrequency ablation¹² or cryotherapy.¹³ These methods use different types of energy to heat up or freeze the tissue surrounding the cancer cells, causing them to die. 

Active monitoring and surveillance of the cancer cells/tumour may also be the first step in the treatment pathway. 

Metastatic renal cell carcinoma 

If RCC has metastasised, the treatment plan may vary compared to localised tumours. More aggressive approaches to treatment and management may be needed, including a combination of targeted drugs, such as immunotherapy and surgical intervention. Metastatic cancer can spread to anywhere in the body; therefore it will present differently in everyone thus, treatment will be individually planned. 

Multiple studies have evaluated the effectiveness of checkpoint immunotherapy, such as Nivolumab, in treating metastatic RCC and have aimed to establish the optimal amount of time to receive the treatment.

The targeted immunotherapy drug, Sunitinib, was the first drug recognised to be effective in improving survival rates amongst metastatic RCC patients.¹⁴ Prior to the development of targeted drug treatment via immunotherapy, cytokine therapy was often regarded as the best treatment option for RCC. However, it produces high levels of toxicity in the body and only has a marginal improvement in overall response and survival rate.¹⁵ Therefore, the introduction of targeted therapy has somewhat revolutionised the management approach to kidney cancer (along with other types of cancers), improving response to therapies and survival rates.¹⁶

Future directions of immunotherapy for kidney cancer 

As well as checkpoint inhibitors, the use of anti-angiogenic drugs is also recognised as a treatment for kidney cancer. Anti-angiogenic drugs block tumours from growing their blood vessels, slowing the growth and occasionally shrinking the cancer. Clinical trials are currently being conducted to investigate the interaction and cooperation of anti-angiogenic drugs used in conjunction with checkpoint inhibitors. It is assumed that we will have a greater understanding of these mechanisms in the coming years; therefore, more targeted approaches to treatment will be available.¹⁷

Additionally, there is continuous research into alternative second treatment options, including clinical trials assessing the efficacy of oral inhibitor drugs (such as RECORD-1 trial).¹⁸

The potential for advancing our understanding of mechanisms underlying kidney cancer and the ongoing development of immunotherapy drugs and combinations with other therapies is expansive, with continuous daily research poured into this field. 

Summary

Kidney cancer occurs when abnormal cells in the kidneys begin to grow and multiply at uncontrollable rates, and the most common type of kidney cancer is clear-cell renal carcinoma. Kidney cancer diagnosis is done via imaging and biopsy of the suspected cancer, and anatomical assessment of the tumour can be a valuable prognostic tool. 

Immunotherapy boosts the body's immune system to help it recognise better and attack cancerous cells. T-cells in the immune system are important for identifying foreign cells in the body, and on their surface, they contain proteins, which cancerous cells can use to hide and go undetected in the body. Immunotherapy drugs, known as checkpoint inhibitors, block these proteins and boost the immune response against cancer cells. 

The use and duration of immunotherapy treatment for kidney cancer will depend on the localisation of the tumour and its extent. It will often be administered alongside other forms of treatment, such as surgical intervention.