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.