“There is a ‘can’ in cancer, because we CAN beat it!” — National Foundation for Cancer Research
From the paper: “Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy”.
When the topic of cancer treatment is discussed, most people will think about chemotherapy and radiation. However, despite being one of the most promising avenues for future cancer therapy, manipulating the immune system as treatment is not ‘well-known’. This could be due to the complex science behind such treatments. Here, we will try to breakdown the research of the most cited cancer research paper into a simple idea that is very important for the future of cancer research.
But how can the immune system be used to stop cancer? The concept behind it uses ‘immune checkpoints’. Immune checkpoints are molecules within the immune system that prevents the body from attacking healthy cells (8). They can be viewed as regulatory molecules that control the behaviour of the immune system. Two important immune checkpoint molecules are CTLA-4 and PD-1, which are present on different types of cells. CTLA-4 and PD-1 will downregulate the immune system, meaning that cells are not attacked in an immune response when they are activated. In disease or infection, these cells should become ‘un-activated’ to allow an immune response. However, in some cancers such as advanced melanomas, these immune checkpoints will remain activated, resulting in tumours and cancer disease progression. Researchers have looked into the possibility that blocking molecules such as CTLA-4 and PD-1 will lead to tumour regression and cancer treatment. Thus, coining the phrase ‘immune checkpoint blockade’ for cancer therapy.
Immune Checkpoint Molecules
CTLA-4 is a receptor that decreases the activity of the immune cells (2), making the body more prone to diseases and infection. If someone has fallen ill, then we don’t want CTLA-4 to be operating as this will prolong the time of illness. To make matters worse, if CTLA-4 interacts with a group of ‘cluster of differentiation’ or ‘CD’ molecules, then the effect of CTLA-4 is stronger making the immune response even less likely to function correctly (3). There are different types of CD molecules, all with slightly different functions and all given different numbers. The CD molecules involved with CTLA-4 are CD28, CD80 and CD86. These three CD molecules are involved in specific immune cell survival and activation (3). When bound to CTLA-4, these CD molecules do not work because of the stronger down-regulatory effect CTLA-4 has on these molecules. We do not want CTLA-4 to interact with CD28, CD80 or CD86. In some cancers, CTLA-4 is upregulated (so there is more of it) in immune cells resulting in a weak immune response towards the disease causing tumour and cancer progression. This effect is heightened when interacting with CD molecules.
The other important immune checkpoint molecule, PD-1 (programmed cell death protein 1) is a protein that also decreases the activity of the immune system by preventing immune cell activation (1). In some cancers, such as B cell lymphomas, PD-1 will bind to a molecule called PD-L1, that prevents an immune response to cancer tumours. Hopefully, we do not want to have PD-L1 interacting with PD-1 but this can happen when some cancers increase the amount of PD-L1 in immune cells. This can happen by two different mechanisms:
- Intrinsic mechanism – Differences in people’s genetics can increase the presence of PD-L1 within the immune system.
- Adaptive resistance mechanism – The presence of other molecules can increase the amount of PD-L1 within the immune system.
But What Did the Researchers Find Out?
What the researchers found out about CTLA-4 and PD-1 during their investigation is presented in the table below.
Drugs that Block CTLA-4 and PD-1
In order to treat specific cancers, we need to block the action of CTLA-4 and PD-1 on immune cells to allow these immune cells to act on tumours. Thus, CTLA-4 and PD-1 blocking drugs have been developed. Ipilimumab is a CTLA-4 blocking drug that prevents a large presence of CTLA-4 on immune cells. Ipilimumab has been shown to increase survival in melanoma patients by 20%, and in some cases, increasing cancer survival by 10 years. Despite being a successful drug for melanomas, ipilimumab only has moderate effects on kidney, lung and prostate cancers but research is taking place to battle these cancer types with immunotherapy. Research into CTLA-4 blocking drugs has resulted in two other important findings:
- A new category of side effects that are caused by negative effects of the drugs on the immune system. In severe cases, up to 30% of patients die due to these effects.
- A new category of clinical response based on immune system-related responses to the drugs.
These findings are important in a hospital setting to aid in the treatment of cancer and in improving the quality of life of cancer patients.
Drugs that block PD-1, such as nivolumab, have a greater effect on tumours and are less toxic than CTLA-4 blocking drugs. PD-1 blocking drugs have a greater range of cancer types that they can affect, resulting in the consensus that PD-1 is the primary target in immuno-cancer therapy. It has also been shown that positive effects of PD-1 blocking drugs last longer than CTLA-4 blocking drugs. Therefore, immunotherapy treatments are currently focused on blocking PD-1.
Although promising, most patients undergoing PD-1 immunotherapy only have partial tumour regression. It has been suggested that immunotherapies with CTLA-4 and PD-1 need to be combined along with other drugs and inhibitors to fully treat tumours. Nevertheless, it is clear that the key to cancer treatment could lie within the success of immunotherapies. Researchers are currently working to create the optimum immunotherapy for all types of cancers. Despite early promise, it could still take years before we have a ‘perfect’ therapy for cancer. With advancing technologies in medicine, we may see significant outcomes sooner rather than later.
— By Daniel Baird
(1) Bio-Rad. “The Role of Immune Checkpoints in Immunity and Cancer,” n.d. https://www.bio-rad-antibodies.com/immune-checkpoint-minireview.html#top.
(2) Syn, Nicholas L, Michele W L Teng, Tony S K Mok, and Ross A Soo. “De-Novo and Acquired Resistance to Immune Checkpoint Targeting.” The Lancet Oncology 18, no. 12 (December 2017): e731–41. https://doi.org/10.1016/S1470-2045(17)30607-1.
(3) Chan, J. K. C., C. S. Ng, and P. K. Hui. “A Simple Guide to the Terminology and Application of Leucocyte Monoclonal Antibodies.” Histopathology 12, no. 5 (May 1988): 461–80. https://doi.org/10.1111/j.1365-2559.1988.tb01967.x.
Featured image from: https://health.clevelandclinic.org/how-your-own-immune-system-can-be-used-to-fight-cancer/