by Mitchell Yeary, '19
In discussing cancer, we often refer to it as a singular disease, much like we would talk about the Spanish Influenza, or meningitis. This gives rise to the common misconception, that there is a single cure to cancer. Of course, if we invented nano-bots that could perfectly repair our DNA in every cell, then a lot of our problems would be solved, including cancer. But for the most part, the faltering and bounding progress we have made asymmetrically affects different types of cancer, leaving some types of cancers with much worse prognosis than others. To give a sense for this, prognosis ranges from 99% 5 year survival for prostate cancer, to as low as 7% 5 year survival for pancreatic cancer.
Over the past decade, the introduction of check-point inhibitors dramatically improved the outlook for patients with a cancer type that may not have previously been treatable, by providing a large range for cancer diagnoses. This was such a revolution, in fact, that it resulted in James Allison and Tasuku Honjo winning this year’s Nobel Prize in Physiology and Medicine.
Honjo on left, Allison on right.
Before diving into how check point inhibitors work, and to what extent they constitute one of the many cures we will continue to discover, it is useful to review some background on what cancer is at the cellular level.
Cancer can arise for many different reasons, which is a vague yet completely necessary sentence to start with. Necessary because there are hundreds of different genes that are associated with the different cancer types, and mutations in these genes can happen for a myriad of different reasons. Likely the most common contributor to genetic mutations is simply age; as we get older, our cells have had to divide a large number of times, making a random mutation that arose from an error in copying over the DNA more likely. Other factors can of course contribute to and accelerate the rate at which errors are made. Factors such as excessive drinking, smoking tobacco, exposure to radiation, and certain chemicals can have carcinogenic (cancer causing) effects. All this is to say that any given cancer cell doesn’t necessarily look the same, but instead these cells operates internally in slightly different ways, and express various surface proteins to their membrane. However, they all do act abnormally within the context of your body.
The question then becomes, why doesn’t our immune system, which is designed to eliminate abnormalities within our body, just kill these harmful cells. The honest answer is that we think they do, and that they do it often. There are, however, some cells that are undetected by your immune system, or have evolved to inhibit immune activity. The second is more common in a cancer that has high mutational burden (meaning a lot of genes are mutated) because this cancer would be making more abnormal biomolecules than the average cancer. With the higher level of unnatural biomolecules, the cancer would be found out if it didn’t evolve a strategy to Jedi mind trick the immune cells that would normally kill it.
This brings us to check-point inhibitors, which are surface molecules that interact with nearby immune cells, and make it clear that the cell they are on is friendly and shouldn’t be killed. It is important, biologically, that other cells have a way of telling roaming immune cells that they shouldn’t be killed. Otherwise, our immune cells would kill indiscriminately, and we would have other issues (such as autoimmune disorders like Type I diabetes and Lupus). It is these signals that cancer cells express to escape notice.
Figure courtesy of New York Times.
We have hypothesized the existence of check-point inhibitors for almost a century, but it wasn’t until Allison discovered CTLA-4 that we were able to develop therapies targeting these molecules. The logic is that if we target the check-point inhibitors with antibodies (basically molecules you can design to stick to specific proteins) made in a lab then the check-point inhibitors found on cancer cells cannot inhibit the immune system, enabling the cancer cells to be killed.
An immediate issue that might come to mind is, ‘OK, your immune systems kills the cancer, but doesn’t it kill your own cells as it does in autoimmune disorders’. First off, I applaud the sly use of my own words against me. But to actually address the question, there might be higher levels of off-target killings, but the cancer is going to be killed at much higher rates than your own cells. This is because all of your normal cells will digest some small amount of their internal molecules (i.e. the assortment of proteins and other biomolecules performing their normal function in the cell), and present them externally. By randomly sampling, this system is designed to catch any invaders that made it into the cell. At some point, the random degradation and presentation will be of the foreign molecule. It is only really when a foreign fragment is present that the immune system kicks into gear. There are exceptions to this, but generally speaking, the immune system does a pretty good job of picking the right cells, even without the check-point inhibitors to help them out.
This work has progressed to the point that it is an integral part of a number of cancer treatments, and has been effectively a cure for a number of patients. The research into additional possible check-point inhibitor targets, and potent combinations is ongoing. There are even drugs being developed that modify the tumor microenvironment to make these immune-oncology therapeutics more effective. The field will continue to develop and lead to exciting advances, pushing us ever further in the fight against death.
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