Certain white blood cells in the body, called T–cells, check and destroy enemy cells such as bacteria and cancer cells. However, a mechanism called immune checkpoint prevents T–cells from killing all cancer cells, and allows the cancer to linger on.
Dr Allison and Dr Honjo found the proteins on cancer cells that act as such checkpoints. For this, they won the Nobel Prize in Medicine in 2018.
A new class of medicines called Checkpoint Inhibitors have emerged out of this research. They are very effective against certain cancers.
Along with the three pillars of cancer treatment, viz., chemotherapy, radiation therapy, and surgery, we now have the fourth way of treating cancer: immunotherapy. All thanks to these pioneering researchers.
Read the full article for this fascinating research story.
Cancer treatments are broadly divided into three types: chemotherapy, radiation therapy, and surgery. Some people call these ‘poisoning’, ‘burning’, and ‘cutting’ the body, in a derogatory or demeaning way.
Of course, there are a few other, less common, types of treatments, such as hormonal treatment in prostate cancer.
Thanks to pioneers such as Dr James Allison and Dr Tasuku Hojo, we now have a fourth type of treatment: Immunotherapy. Their research found out how to use our body’s immune system to kill cancer cells.
For this brilliant scientific work, they won the Nobel Prize for Medicine in 2018.
The concept of ‘immune checkpoints’
How does our immune system work
Our body’s immune system involves different types of white blood cells that detect and destroy foreign substances.
Here is a YouTube video containing a simple animated explanation of how our body’s immune system works.
T–cells are one type of white blood cells that determine our immune response to foreign substances (antigens) in the body. They are like the special forces, or military, in the body. They do not indulge in the regular law and order (immunity) situations. They stay on the sidelines till a serious problem is encountered.
T–cells have various proteins on the surface of their cell membranes. When a T–cell encounters another living cell, which could be an external bacteria cell, an internal normal cell, or an internal cancerous cell, it looks for certain proteins on the surface of that cell.
Read here, in a fairly complicated, but comprehensive, terms: How do T–cells work?
If the protein on the surface of a T–cell binds, or attaches properly, to the protein on the surface of the cell it verifies, it is considered to be an acceptable cell.
This is equivalent of the office security personnel checking the identity cards of persons they encounter. If a valid ID card is found, the person carrying it is considered safe and allowed to proceed.
There are various types of T–cells, who carry different proteins on their surfaces and hence, are able to detect all the normal cells in the body.
The T–cells destroy damaged body cells after checking if those cells have the right proteins on their surface. Cells that do not produce those proteins are considered defective and are destroyed. Since cancer cells are, in a way, defective, T–cells can be used to detect and kill cancer cells.
How tumours evade detection by our immune system
Since T–cell action can get out of control, the body insists on receiving two ‘enemy’ signals, not one, before the T–cells can get into action.
The first signal is generated by the presence of foreign substances (antigens). However, the second signal comes only when a certain protein on T–cell surface, CD28, attaches to two proteins, B7–1 and B7–2 on the surface of antigen–presenting (potential enemy) cells. After receiving both these signals, T–cells get into action.
Cancer tumour cells are able to evade detection by the immune system. They don’t activate the CD28 protein attachment to B7 proteins. As a result, the body’s immune system does not even find the cancer cells until the tumour grows big enough to cause damage.
At that point, the tumour cannot get enough nutrients or oxygen through the blood. So, some of the tumour cells start dying. This causes inflammation, which informs the immune system of the presence of cancer.
Why do we have immune checkpoints
Once activated, the T–cells are supposed to kill cancer tumour cells fully. However, to prevent our immune response from going haywire, the body has a mechanism to tone down the T–cell attack after some time. It is called an Immune Checkpoint.
As a part of the checkpoint mechanism, the T–cells also have a protein called CTLA–4, on the surface of their membranes. Cancer cells have B7–1 and B7–2 proteins on their cell membranes. When the T–cells come in contact with the cancer cells, CTLA–4 attaches to B7 proteins. If this happens properly, the T–cells start reducing their action and leave the cancer cell alone.
In other words, CTLA–4 provides a way to stop the body’s immune action of killing cancer cells. CTLA–4 is, thus, a checkpoint protein.
Dr Allison found out the protein that triggers T–cells into action (CD28), as well as the one that stops the T–cell action (CTLA–4).
Dr Honjo discovered another protein on the surface of the T–cells, called Programmed Cell Death–1 (PD–1), which also stops the T-cell response to cancer cells. PD–1 does that by attaching to another protein, called PD–L1, on the surface of the tumour cells.
Thus, PD–1 is another checkpoint protein, though it is specifically named Programmed Cell Death protein.
In essence, once triggered as above, the T cells go about killing cancer cells in the tumour. However, some time later, the proteins, CTLA-4 or PD-1, stop the T cells before their response goes out of control.
If the T–cells kill all the cancer cells before CTLA–4 or PD–1 kick in, then the immune system wins over the cancer. If CTLA–4 or PD–1 turn off the T–cell action before all the cancer cells are destroyed, then the cancer wins.
This is the concept of the fourth approach to cancer treatment — using the immune system to attack cancer, rather than attacking it directly.
New medicines stopping checkpoints
In theory, if some medicine can block CTLA–4 and PD–1, that medicine will allow T–cells to kill all cancer tumour cells. In practice, such medicines have to make sure that they allow T–cells to kill all cancer cells but somehow, not allow the T–cells to get out of control and damage organs in the body. In short, they should have limited side effects.
Luckily, such medicines are slowly seeing the light of the day.
New medicines that block CTLA–4 are called Checkpoint Inhibitors and those that block PD–1 are called Programmed Cell Death Inhibitors. Spectacular results have been observed in advanced and metastatic (spread to other organs) cancers.
The checkpoint inhibitors are now approved for six late-stage cancers — melanoma, lung cancer, renal cell carcinoma, head and neck cancer, urothelial cancer, and Hodgkin’s lymphoma — with many other cancers being investigated in clinical trials.
American Society of Clinical Oncology (ASCO) hailed this immunotherapy as a clinical cancer research advance for 2 years in a row.
Read the interesting story of Dr Allison’s discovery: The search for the cure for cancer. The story was published in 2016 and it predicted Dr Allison would win the Nobel Prize, which happened in 2018.
Brilliant science. Decades of solid research. Worthy of the Nobel Prize.
“Fifty years from now, it’ll be unusual for someone to die of cancer — it’ll be like pneumonia. It is our hope that we can compress that time to more like ten or fifteen years” — Patrick Hwu, a melanoma oncologist at MD Anderson, USA
First published on: 6th October, 2018
Image mandatory credit: Kyodo/MD Anderson Cancer Center at The University of Texas/Handouts via REUTERS