There were 18.1 million new cases of cancer and 9.6 million deaths caused by cancer in 2018, according to the World Health Organization (WHO). From such numbers, the topic begs the question, why are we so defenseless against cancer, and can’t we do anything significant to increase our chances of survival?
Well, we certainly aren’t defenseless. Cancer isn’t a brand new threat that appeared out of nowhere and started terrorizing humans. It's an ancient condition found in not only humans but other biological organisms (including plants, although they are slightly less vulnerable), that has become more prevalent today with the introduction of new factors that increase the chances of cancer; recent advances in technology and resulting shifts in lifestyle, frequent smoking, etc. Over the years of evolution, organisms have developed ways to deal with cancerous tumors.
Our body possesses special immune cells called T cells, which are produced primarily within the thymus specializing in the recognition of foreign particles and combating them. These cells bind to other cells’ T cell receptors which are groups of proteins on the surface that present the T cell with certain molecules. Normal cells present the T cell with the proper molecules, whereas cancerous cells present the T cell with a foreign particle, also called an antigen. Once the T cell recognizes an antigen and the cancerous cell fails to pass this checkpoint, it sends a message to the nucleus of the cancerous cell ordering it to kill itself.
Of course, if this method was 100% fool-proof, cancer wouldn’t be so prolific today. Cancer cells can bypass this “test” by handing the T-cell inhibitors, or molecules that bind to the T-cell’s receptors and inhibit its ability to message the nucleus. Examples include PD-L1, a ligand/protein that binds to the T-cell’s PD-1 (Programmed cell Death protein 1) and prevents the T-cell from killing the cancer cell.
To counter this, immune checkpoint inhibitors (ICIs) were developed by humans. ICI’s are important drugs for those afflicted with different types of cancers, whether it be malignant melanoma (a cancer of pigment-carrying skin cells), lung cancer, kidney cancer, bladder cancer, and much more. ICI’s make T-Cells simply ignore the test they give cancerous cells and simply kill them. The ICI’s bind to the specific receptors of the T-Cell and prevent the cancer cells’ ligand from attaching, forcing the T-Cell to ignore this checkpoint and simply initiate the immune response. In a way, ICI’s are like inhibitors of inhibitors. They prevent the cancerous cell’s inhibitors from binding to the T-cell’s receptors by binding itself to the T-cell beforehand and causing it to kill the cancerous cells without being inhibited.
Ipilimumab was the first approved immune checkpoint inhibitor for treating patients with advanced melanoma/skin cancer. Approved by the US Food and Drug Administration in 2011, It targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein immune checkpoint that can be bypassed by the cancer cells through CD80/CD86 ligands. This antibody prevents T-cell inhibition and promotes the activation and proliferation of effector T cells. Ipilimumab proved to be very effective, and earned approval as a potent solution against cancerous tumors. The success of Ipilimumab lead to the examination of other antibodies that target immune checkpoints and the creation of other effective ICIs. For example, Pembrolizumab and nivolumab, ICIs that target programmed death-1 (PD-1), showed promising results in melanoma and non-small cell lung carcinoma patients. As of now, hundreds of clinical trials for phase 1, 2, 3, and 4 cancer patients are being carried out across the globe to evaluate the efficacy of multiple ICIs, and ways to utilize such drugs efficiently (e.g. using combinations of ICI’s vs applying one at a time).
ICI’s themselves are a revolutionary advancement in the field of oncology. They make cancer cells more vulnerable to our human immune system, opening up ways for other treatment options. So are ICI’s a perfectly fine counter to cancer? Well, considering how death by cancer is still very prevalent today, you can infer that ICI’s aren’t a seamless barrier to cancer. Research shows that ICI’s are in fact far from being perfect.
To start off with, there are simply too many factors that determine how effective an ICI is in an individual’s body, and the ways for cancer cells to gain T-Cell Immunity are too diverse or varied for ICI’s to completely prevent cancer. ICI’s merely prevent cancer cells from bypassing immune checkpoints of t-cells. There are numerous other methods to prevent the immune system from noticing and combating the cancer. For example, some cancers are known to simply inhibit the presence of T-cells around the cancerous tissue. However, this in itself is not necessarily a disadvantage of ICI’s; cures to a disease are often never complete without the use of other complements. ICI’s are simply a piece of the larger puzzle named “The Cure to Cancer.” Developing ICI’s have brought us closer to that achievement.
Some issues of ICI’s lie in the ICI’s themselves. ICI’s have been shown to be highly toxic to the human body, and that they are able to cause severe inflammatory effects. These side-effects are designated as irAEs, which stands for immune related adverse effects. irAE’s affect practically all parts of the body, but the stomach, intestines, liver, endocrine glands, and the skin suffer the worst. The gastrointestinal tract suffers from colitis(inflammation of the large intestine), and enteritis(inflammation of the small intestine). The liver suffers from hepatitis(inflammation of liver), causing vomiting, tiredness, poor appetite, and more. The skin develops rashes and vitiligo(loss of skin color). Besides that, there is a large plethora of symptoms ICI’s bring, varying in fatality, but all quite unpleasant.
Why do irAE’s occur then? Inflammation in itself is an immune response that heats up the body to help repel foreign pathogens such as bacteria. It is designed to create harsh conditions that make it difficult for the pathogen to proliferate. When there are no foreign threats, there is no inflammation, as such conditions aren’t optimal for our cells as well. However, ICI’s can cause a “false alarm.” Altering the immune system, as ICI’s do, can cause great increases in the immune system’s security, one effect of which is inflammation. Essentially, ICI’s remove the checkpoints that need to be passed for the immune system to improve its security - and kill the cancer cells whether or not the immune system recognizes them.
However these checkpoints exist for a reason. Increasing the immune system’s security is costly in terms of energy usage, and in the case of inflammation it greatly disturbs various processes, such as enzyme activity (after all it was designed to do the same against foreign intruders), within the human body as well as cause uncomfortable side-effects.
Considering the severity of the side effects ICI’s can cause, we must take greater care and attention towards their usage. Decreasing the toxicity of the ICI’s themselves is a top priority for those in the study of immunotherapy. As for now, all we can do about irAE’s is to prescribe drugs to ameliorate the side effects of inflammation that come with the application of ICI’s. But perhaps more important is to continue with the research of ways to prevent cancer caused by different causes. After all, ICI’s only deal with one method of cancer proliferation.
While not complete counters to cancer, ICI’s themselves have proven themselves to be an effective measure. They are a taste of what’s to come with the ongoing development of oncology, and display promising results. The cure to cancer has never been about the creation of a single prescription drug, but rather the outlining of a treatment program with multiple processes that all interact together to put an end to cancer. The development of ICI’s means that we have found one of the possible processes that are crucial to the discovery of the cure, and in the near future, we will be able to discover the remaining processes and prevent cancer from causing any more deaths in the human population.
Works Cited
Darvin, P., Toor, S. M., Nair, V. S., & Elkord, E. (2018). Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental & Molecular Medicine, 50(12). doi: 10.1038/s12276-018-0191-1
Azoury, S., Straughan, D., & Shukla, V. (2015). Immune Checkpoint Inhibitors for Cancer Therapy: Clinical Efficacy and Safety. Current Cancer Drug Targets, 15(6), 452–462. doi: 10.2174/156800961506150805145120
Immune checkpoint inhibitors to treat cancer. (2018, October 1). Retrieved from https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html
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