Blinded by Science blog 14: What is cancer immunotherapy and how does it work?

Cancer sucks!

Yeah. Not the most earth-shattering revelation I could begin my first blog entry with in almost two years, but it’s been a bit rough recently. Within the past week (of the start of my writing this entry, because let’s be real, who knows when I’ll actually post this), as part of my job, I have been present for three separate patients to get the bad news that their cancer had progressed and that we would have to take them off the clinical trials they were participating in. (*Edit* Two of those patients have since passed away. Sometimes cancer works way too fast.)

Being there for that is hard. Now I’m not trying so say that my discomfort is somehow on the same level as what the patients and their family went through. It isn’t and I hope that I never have to experience what they went through. But that doesn’t mean that I didn’t feel anything either. While I can’t say that I play a role in actually treating patients, I do interact with patients, form relationships with them, and become invested in their outcomes. So when setbacks occur, it hurts. Despite that, I hope I never become numb to those feelings.

So in honor of those feelings and those patients, this blog post is going to break from the mold of my other posts (if you can count only 13 other posts as having a mold) and I am actually going to answer one of my own questions.

So Tony asks, “In the context of cancer treatment, what is immunotherapy and how does it work?”

Great question Tony!

Yeah. That’s enough of that.

Immunotherapy, with regards to cancer treatment, is a category of therapy that can potentially describe a couple of different types of treatments. According to the American Cancer Society, “Immunotherapy is treatment that uses your body's own immune system to help fight cancer.” Types of immunotherapy include monoclonal antibodies, CAR T cell therapies, immune checkpoint inhibitors, cancer vaccines, and non-specific cancer immunotherapies and adjuvants. I’ll describe each a little bit, but I’ll be focusing the majority of this post on the immune checkpoint inhibitors. Also, the immune system is a ridiculously complicated topic so I am going to endeavor to explain everything in as succinct a way as possible without going into too much detail. I’ll save the more in depth explanation of the immune system and how it works for other potential posts.

Let’s start with the monoclonal antibodies. To start with, I’m only going to give a very broad explanation of antibodies and how they work. A thorough explanation would require not only a post dedicated to antibodies themselves, but also a couple posts dedicated to the overall immune system itself. Antibodies are proteins created by the immune system (specifically B cells as part of the humoral immune response), which are able to bind to very specific shapes of proteins on the surface of cells, or bacteria, or viruses, etc. Without getting into specifics, their central role as part of the immune response is why they make such useful therapeutic tools in oncology.

Once bound to these very specific target molecules, antibodies can cause a variety of effects including: marking the target to be engulfed by other immune cells, calling immune chemicals over to destroy the target, or directly neutralizing the activity of the target so it can’t function. Monoclonal antibodies are designed in the lab to target specific molecules and many copies of these antibodies can be produced. These antibodies can function alone to create the effects I listed above, or they can be bound to chemicals or radioactive molecules to deliver this “payload” to the cancer directly, sparing a greater amount of healthy tissue from the effects of these destructive compounds. Think of it as using a cruise missile against a target instead of just carpet bombing the whole area.

CAR T cell therapies are another type of immune therapy. CAR T cell therapy stands for Chimeric Antigen Receptor T cell therapy. T cells, which are a type of immune cell, are capable of recognizing foreign material in the body and directing the immune response towards it. Cancer cells tend to look very similar to healthy cells, which makes it very difficult for the immune system to recognize these dangerous cells and attack them. In CAR T cell therapy, T cells are removed from the patient’s body. Within a laboratory, specifically designed receptors (the parts of the T cell that are able to recognize the target) are inserted into the T cells. These receptors allow the T cells to recognize the cancer cells and mount an immune response to the disease. These manipulated cells are then put back into the body where they seek out tumor cells and activate the patient’s immune system against them. 

Cancer vaccines work very similarly to other types of vaccines, they train the immune system to fight against specific targets. In some cases, the development of certain types of cancers have been linked to infection by certain viruses (ex. HPV or Hepatitis B). Therefore, becoming vaccinated against these types of viruses has been shown to decrease the chances of developing those types of cancers. But these are types of vaccines that prevent cancer. There are also vaccines that help the body fight cancer that has already developed. Some of these vaccines take parts of cancer cells, purify them, and then inject them back into the body in an effort to get the immune system to recognize the cancer as something that needs to be attacked. Still another type of vaccine is one that currently is only approved for use in advanced prostate cancer (Sipuleucel-T also known as Provenge). Immune cells are harvested from the patient and changed in the lab into special immune cells called dendritic cells. These cells are then exposed to a chemical that should cause the immune system to target the prostate cancer. While this type of vaccine does not cure the patients, it has been shown to extend their lives by several months.

Non-specific cancer immunotherapies and adjuvants basically just ramp up the immune response in general, which can help fight off the cancer. Interferons and interleukins are two types of immune signaling molecules. Some members of these families currently used in cancer treatment are interleukin-2 and interferon-alpha. Ramping up the immune response is especially useful because many cancers create an environment around themselves that dampens down the immune system, as a sort of protection for the cancer, which actually brings me to my last (and for the sake of this post), most important type of cancer immunotherapy.

Now to finally discuss immune checkpoint inhibitors. To be fair, immune checkpoint inhibitors are often monoclonal antibodies, so this section could really go up underneath that type of treatment as a subset. But I think that they need their own explanation, and this is my blog, so I can do what I want. So there!

Anyway, to understand checkpoint inhibitors, you must first understand a little of how the immune response works. In very general terms, I think it would be helpful if you could think of the immune response to a pathogen as being split into three phases. You have the recognition phase where the immune system realizes that a pathogen is present, then you have the expansion phase where the response ramps up as immune cells begin to divide rapidly and fight the pathogens, and finally the contraction phase where the immune response tapers down and goes back to standby once the pathogen is gone. To keep everything working properly and under control, checkpoints exist that need to be passed for the immune response to shift between these phases. The shift from the expansion phase to the contraction phase is particularly important. If the immune response lasts too long, it can cause damage to the surrounding tissue or throughout the body. Autoimmune diseases, such as rheumatoid arthritis, are examples of what happens when the immune system damages the body.

The molecules PD-1 (1, 2) (Programmed Cell Death-1) and PD-L1 (Programmed Cell Death Ligand-1) and are part of an important checkpoint to make this shift. Basically, PD-L1 is expressed on your own cells and when T cells (which express PD-1) interact with it, the T cell shuts down. Cancer cells can use this pathway to protect themselves from the immune system. By over-expressing PD-L1 on their surface, cancer cells effectively put the brakes on the immune response that would target the cancer, so now the cancer cells can hide from the immune system and grow unimpeded.

It is this strategy that immune checkpoint inhibitors target. Monoclonal antibodies (which we learned about earlier) target either PD-1 or PD-L1 and block the binding that is necessary to shut the T cells down. In essence, these antibodies cut the brake lines of the immune system. Or in other words, the tumor that was previously hidden from the immune system is now revealed. Examples of PD-1 inhibitors are Pembrolizumab (Keytruda) and Nivolumab (Opdivo) while examples of PD-L1 inhibitors are Avelumab (Bavencio) and Durvalumab (Imfinzi). Ipilimumab (Yervoy), is another immune checkpoint inhibitor that targets a different protein, this one being CTLA-4, which also can shut down the immune system. These treatments are currently approved for multiple cancer types while still undergoing studies on other types.

Immune checkpoint inhibitors are powerful, but are not perfect. Even before getting into side effects, these drugs only have a chance of showing their effectiveness in cancers that utilize their targeted pathway to evade the immune response (PD-1/PD-L1 or CTLA-4). Also, even if the tumor depends on these evasion pathways, blocking the pathway may not lead to recognition of the tumor by the immune system (this is known as immune evasion). For cancers that don’t utilize these pathways, immune checkpoint inhibitors can easily be ineffective. And like all drugs, they come with side effects. Some are common and relatively minor: nausea, coughing, fatigue, rash, or even itching. But there can be more severe ones as well, which are often due to over activity of the immune system that results in damage to normal tissues. As I mentioned earlier, using checkpoint inhibitors is like cutting the brake lines. Sure, now tumors can’t hide from the immune system, but the immune system works throughout the body, which means it could run out of control and damage healthy tissue elsewhere. Also, there is some data that suggests that people with certain types of T cell cancers, if they were to be treated with anti-PD-1 drugs, might have their cancers become even worse. These issues make for a careful balancing act that doctors have to go through when treating cancer.

Blinded by Science blog 13: Feeling of going downhill while driving uphill

Today on Blinded by Science, what do mountainous roads and striped dresses have in common?  Read on and find out.

Chris G asks, “When I drive in the mountains it sometimes seems like I am going down hill when actually I am still going up. How does that happen? Has this ever happened to you?”

To answer your last question first, no I don’t think it has ever happened to me.  But then I tend to zone out whenever I drive anyway, so I probably wouldn’t remember if it had ever happened to me.

Wait . . . that’s probably something I should not admit out loud.

 

What I meant to say was that because I drive so very defensively, I am always aware of what is happening on the road around me and the conditions of the road itself so I would already know that actual slope of the road well in advance.

Or more likely, I just don’t drive in the mountains very often so it hasn’t happened to me yet.

Anyway, while trying to research this topic, I think I may have found what you were speaking about.  There is a known optical illusion in which a descending slope appears to be ascending or an ascending slope appears to be descending.

Yashima Driveway, Kagawa Prefecture, Japan; photo by Akiyasu Tomoeda

In the above photo, the section of road in the foreground is descending as is the section of the road in the background (even though it appears to be ascending).  This occurs because a “trough” appears when two sections of road with differing slopes converge.  The trough causes drivers to misjudge the incline of the road.

Well, I’ve answered your question, but frankly I don’t want to post such a short blog post this time (I’m sure there will be times in the future where I will, but not this time!).  So I’m going to add a small explanation of optical illusions and why they occur.

Aren’t I just a wonderful person?!  Money and delicious food are always appropriate ways of showing gratitude.  Just an FYI.

An optical illusion is a perception, as of visual stimuli, that represents what is perceived in a way different from the way it is in reality.  In other words, when your brain perceives the images seen as different from what actually exists.

Remember this dress? Swiked/Tumblr

Basically, your brain has the task of organizing and integrating all the information coming in from your various senses (including sight).  Because of the obscene amount of information coming in, the brain has to take some shortcuts in processing it so as to make something useful out of it and properly interpret the information.  Sometimes, though, due to the nature of the information coming in, the shortcuts cause misinterpretation instead.  This is likely what cause optical illusions to occur.

And because there are many types of shortcuts the brain uses, there are many types of optical illusions.

Well Chris, I hope this helped a bit.

Blinded by Science blog 12: Mercury danger from home CFLs.

We’ve made it to the latter half of April and the weather seems to be finally turning.

Probably turning into this.

With the advent of spring and soon summer, the days are continuing to get longer so you’re probably not turning on lights as often as you did during the fall and winter.  So with my wonderful and obviously appropriate timing, today I will answer a question about compact fluorescent light bulbs (CFLs).

Steve P. asks, “I recently broke a CFL lightbulb in my house.  I know that CFLs contain mercury (although I am not sure what part contains the mercury).  How much mercury was I exposed to from the broken lightbulb?  How does this mercury exposure compare to mercury from eating fish?  Am I going to die?”

To answer this question, it’s probably a good idea to first explain what mercury is and why it is dangerous.  Mercury is a metal, though unlike other metals, it is found as a liquid at room temperature.  This property has caused mercury to be known by another name, quicksilver.

 

Nope. Wrong one.

There we go.

There are a lot of dangers associated with mercury and certain mercury compounds.*  Metallic mercury (elemental mercury), which is the type that is liquid at room temperature, does not tend to pass through intact skin and if swallowed, does not get absorbed readily by the gastrointestinal tract.  However, metallic mercury tends to vaporize quickly and it passes through the lungs into the bloodstream if you breathe this mercury vapor in.  On the other hand, organic mercury compounds like methylmercury are readily absorbed into the body through the gastrointestinal tract.  In general, they are not easily absorbed through intact skin, though there is a form, dimethylmercury, which can rapidly enter the body through the skin.

The nervous system is particularly susceptible to mercury, so health concerns related to mercury exposure include: loss of peripheral vision (methylmercury); impairment of speech, hearing or walking (methylmercury); insomnia (elemental mercury); headaches (elemental mercury); skin rashes (inorganic mercury); or memory loss (inorganic mercury) (1, 2).  Damage to the gastrointestinal tract or to the kidneys can also be the result of mercury exposure.

With regards to sources of mercury exposure, due to the nature of food chains and the way mercury is absorbed by fish, mercury can become concentrated in certain types of fish.  The higher on the food chain the fish is found, the more mercury found in the fish.  In fact, here is a handy table that shows the amount of mercury in various species of fish.  It is important to note that the type of mercury found in fish tends to be methylmercury, which is a highly toxic compound of mercury.  Eating small amounts of fish is unlikely to cause problems for the majority of people (though it is important to limit the amount of fish consumed that are relatively high in the food chain).  However, pregnant women are advised to stay away from certain types of fish during pregnancy because the mercury can cause problems for the developing nervous system.

Due to the physical requirements of creating CFLs, mercury vapor is necessary for the CFL to function.  There is only a small amount of mercury in each light bulb, about 4 milligrams on average.  And when these bulbs are broken, only a tiny fraction of the total mercury is released, though the longer you let the broken bulb stay there without cleaning it up, the more mercury is released.  In other words, as long as you clean up the broken bulb quickly (and according to the appropriate procedures!!), the amount of mercury released will not pose a health hazard.

Also, from what I can find, the type of mercury in CFLs is elemental mercury which is not quite as dangerous or toxic as an organic mercury compound such as the methylmercury found in fish.

So in conclusion, mercury is a dangerous compound, though the extent of the danger and the damage caused is based on the type of mercury compound and the route of exposure.  Methylmercury can be found in the tissues of some fish while small amounts of elemental mercury are found in compact fluorescent light bulbs.  A small percentage of what is found in these light bulbs can be released if the light bulb breaks, though it is not enough to cause worry (though be certain to clean up the broken pieces of the bulb properly and dispose of these pieces properly as well).

Overall, you have less to worry about from the mercury exposure from a broken CFL than you do from the mercury exposure from eating fish, and even that exposure should not cause you much worry as long as you don’t eat too much fish.

*Not every compound containing mercury is equally dangerous.  Ethylmercury, which can be found in thiomersal (thimerosal), has different properties from its more dangerous methylmercury cousin.  I would not be surprised if I get a question that requires me to go more in depth on this in the future, but for now, please understand that different chemical compounds have different physical properties (including toxicity), even if they contain some of the same atoms.

Blinded by Science blog 11: What, if anything, does the father contribute to the epigenome?

Posting the last entry, I realized that I’ve had this blog for over a year.  That’s kinda crazy to think about.  Now I’m not one for introspection . . . okay, that’s a ridiculous lie.  I partake of introspection quite a bit, though it is debatable whether I am able to glean any insights into myself from it.  Wait.  Does that count?  You’ll allow it?  Sweet!

Anyway, it is rather remarkable the differences a year can make.  New city.  New state.  New job.  And yet, some things haven’t changed.  I still really enjoy doing this, communicating science to others.  Hopefully, I am able to continue this with the same level of enjoyment.  And as always, for those of you that read the blog and/or contribute questions, thank you!

Now enough sappiness.  On to the question!

Okay, just a little more sap.

Chris H asks, “Epigenetics is quite the buzz-word of late. What, if anything, does the father contribute to the epigenome? Is it a percentage? Or certain things?”

Yay!  Another biology question!  I really enjoy these.

Before I begin, let’s do a little recap.  Remember how I earlier gave a brief explanation of genetics?  Basically, DNA holds a person’s genetic information; the information is converted to RNA and then translated into proteins which do things for the cell, lots of things.  This whole process, from DNA to RNA to protein to beyond, is very tightly controlled and regulated.  In fact, for most genes, the most important form of control is transcriptional control, which deals with the conversion of the information from DNA to RNA.  This makes sense.  Controlling at this step ensures that the cell does not create unnecessary, and therefore wasteful, intermediates.

One of the methods of transcriptional control is at the level of chromatin structure.  Chromatin is the combination of DNA with proteins and other macromolecules.  It not only protects your DNA but also condenses it so that it can fit inside the nucleus of each of your cells.*  But condensing the DNA enough to fit in the nucleus makes it difficult for the proteins that transcribe the RNA from DNA to read the code and do their job.  So the cell has to loosen the chromatin around genes when they need to be “turned on” and transcribed.  In addition, not all cells need every gene product the genome codes for.  Muscle cells don’t need to make proteins necessary for bone cells, and red blood cells would have problems if they produced the adhesion proteins that keep intestinal cells held to each other without leaking.  So body cells need a way to keep some genes “turned off”.  So the cell will add chemical modifications to the chromatin proteins which cause the structure to loosen (allowing for more gene transcription) or cause the structure to tighten (limiting gene transcription).

Another type of transcriptional control occurs when the chemical structure of the DNA itself is modified.  One of the four DNA bases, cytosine, has a methyl group (a carbon atom that is bonded to three hydrogen atoms) added to it to become 5-Methylcytosine.  It still pairs to guanine, but regions that contain high amounts of this modified base are less active when it comes to transcription.

It is important to understand that neither of these types of control change the underlying DNA code, they merely change the behavior of genes, allowing some to be transcribed more while others are transcribed less.

But what do these transcriptional control mechanisms have to do with the question at hand?  Epigenetics is the study of external or environmental factors that turn genes 'on' and 'off' and affect how cells 'read' genes.  And an epigenetic trait is a “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence”.  So these two transcriptional control mechanisms are examples of epigenetic modifications that occur in a chromosome.

Additionally, due to their nature and purpose, these changes tend to be inherited by the daughter cells after a cell divides.  Amongst other things, this allows a cell to keep certain genes turned off throughout its descendants, which can function as another layer of protection so muscle cells do not produce proteins that are only necessary for bone cells or brain cells produce proteins that are only necessary for liver cells.

But with regards to the question, do these epigenetic markers survive into the next generation?  And the answer is . . . drum roll please . . .

Eh.  Close enough.

Nope.  They do not.  Except when they do.

This is biology we’re talking about.  Exceptions abound.

Normally, after a sperm and an egg meet and fertilization occurs, the epigenetic markers are wiped clean.  Remember that epigenetic markers help silence genes in one cell type that are only used by a different cell type.  So the markers must be removed so that all the different cell types can develop properly (the markers will be replaced as cellular differentiation occurs).  In mammals, it is thought that this process of removal occurs very early in life, just after fertilization.

But some genes keep their epigenetic markers after fertilization.  Imprinted genes are able to keep their epigenetic markers past fertilization (though they are not the only type of genes that can).  Imprinted genes can be inherited from either the father or the mother.  It is currently estimated that about 1% of mammalian genes are imprinted.

As for how much the father contributes to the epigenetic state of the offspring, it is not currently known.  Epigenetics is still a relatively young field of study.  However, it is known that the father does contribute at least some epigenetic markers so it isn’t zero.  My guess (and it is completely a guess since this is not my field of study and I couldn’t find anything about it while researching for this post) is that the father and the mother each contribute roughly the same amount to what little epigenetic markers survive being wiped clean after fertilization.

*It is estimated that each cell in the human body has about 2 meters of DNA in the nucleus.  It is also estimated that there are about 50 trillion cells in the human body.  So there is about 100 trillion meters of DNA in your body, enough (as this source mentions) to make it to the Sun and back more than three hundred time!