5 Questions to Understand Immunotherapy from an Interdisciplinary Perspective
By: Sofiya Kominko
Tags: Cancer, Checkpoint Inhibitors, Immunotherapy, Medicine, Treatment

Credit: Michele Marconi

My first piece about getting access to immunotherapy for my father was one of the toughest articles/reflections that I have ever written. Laying out all of my thoughts forced me relive the experience, over and over again, as I edited and wordsmithed to try and convey what I have been feeling this past year.

While I provided a brief introduction to the world of immunotherapy, I by no means did the subject justice. So I’d like to return to immunotherapy and unpack it some more in the hopes of providing you with some insight if you are new to the subject, like I was just a year ago.

Here is a list of basic Q&A about immunotherapy as a cancer treatment, which can perhaps serve as a humble point of entry into the field from an interdisciplinary perspective.

What is immunotherapy?

While over the years immunotherapy has started to refer more and more to check-point inhibitor drugs, in actuality, immunotherapy is more of an umbrella term for a class of treatments.

These treatments share the same logic in that they work with the immune system to try and create an immune response against a malignant tumour. Rather than seeking to destroy a cancer cell and its genetic makeup (as would chemotherapy or radiation), immunotherapy interferes with the workings of cells, making them capable of recognizing a malignancy.

The most popular type of modern-day immunotherapy (at least in North America) are immune check-point inhibitors. These are drugs administered through an IV (just like chemo) and the most common ones are Pembrolizumab (Keytruda), Nivolumab (Opdivo), Cemiplimab (Libtayo). All three of these drugs work by targeting a protein (PD1) on the T cell — the “killer cell” as you may recall from grade 11 biology, which is responsible for killing an antigen or generating an immune response to it.

The problem that these drugs try to solve involves breaking a particular type of link.

The scenario that is often seen in cancer is that the protein on the t-cell (PD1) will attach itself to a protein (PDL1) on the cancer cell. When this link occurs, the t-cell sort of enters a toxic relationship with the cancer cell — it binds to it without being able to recognize that it needs to leave, which would bring back to the t-cell its normal function — the drive to kill the antigen. As a side note, no suggestion here that one should kill their ex once they leave a toxic relationship.

The new set of aforementioned drugs are so intricately designed that they can actually break this link between the PD1 and PDL1, returning the body’s natural abillity to fight back.

To be able to problem solve at this level of detail is quite a remarkable achievement and for this, James P. Allison, PhD and Tasuku Honjo, M.D., Ph.D. — the fathers of modern-day immunotherapy received the first Nobel Prize given for a cancer therapy in 28 years. Allison and Honjo first made the discovery about a different type of protein (CTLA-4) but their discoveries soon led to drugs targeting the PD1-PD1L link.

While checkpoint inhibitor drugs are the most common and commercialized type of immunotherapies, I will briefly mention the others.

These include t-cell therapy, where doctors remove t-cells from a patient’s blood, modify the t-cells in a lab, and insert the t-cells back into the blood with a new capability for them to fight back. There are also cancer vaccines, oncolytic viruses, centrifugal elutriation, and target therapies — all fascinating lines of therapies, which merit separate attention.

While the mechanisms may be different, all immunotherapies’ logic is the same — work with the body rather than against it. This shift in thinking is a drastic change in the world of oncology, which has been preoccupied with the ruthless destruction of cells for most of the last century.

Perhaps it is this shift in thinking that excites me most about immunotherapy.

2. How long has immunotherapy been around for?

I go into the history of immunotherapy in my first piece. In short, early forms of immunotherapy have been around since the late 19th century. Many scientists and researchers have also discovered viruses or bacteria such as Coley’s toxins along the way, which in one way or another stimulated an immune response.

However, check-point inhibitors are a new class of drugs, with the first one being approved by the FDA in 2011 (ipilimumab) for the treatment of melanoma. A suite of other check-point inhibitors for other types of cancers followed and have been in continuous development ever since.

3. What are the side effects of immunotherapy?

During my conversations with oncologists, immunotherapy was presented to me as the lesser of two evils, that is in reference to the side effects caused by chemo.

Side effects from check-point inhibitor drugs are presumably far less worse than from chemo agents, but I did not have the luxury to observe my father’s reaction to them. My father’s reaction to chemo? Hell.

According to American Cancer Society, the common side effects for check-point inhibitors include: diarrhea, pneumonitis (inflammation in the lungs), rashes and itchiness, problems with some hormone levels, and kidney infections.

There is no mention of extreme fatigue (the type where you cannot get out of bed) or nausea, which is almost inevitable with pretty much any chemo agent.

Once again, although I have no personal experience, anecdotal evidence from our spindle cell sarcoma and UPS support group shows that people can more or less go about their normal lives while receiving this treatment (although, reaction to any treatment is always very individual).

Based on my research and conversations, the conclusion that I’ve come to is that immunotherapy is really the lesser of two evils and may have a potential for sanctity.

4. Is immunotherapy actually effective?

This is the million dollar question. And it is difficult to answer definitively without first setting out a few conditions.

First, immunotherapy is effective in some cancers more than others. For example, patients with advanced (metastatic) lung, bladder, and skin cancers tend to respond better to the immunotherapies that have been developed to date for these specific cancers.

Beyond specific cancer types, research has shown that immunotherapies seem to work best in people who exhibit higher levels of PD-L1 proteins — the very protein that an immunotherapy like Pembrolizumab targets, although some people may show a response without having great expressions of these proteins, so as always, things are nuanced.

Guru P. Sonpavde, MD, a contributor to Harvard Medical Publishing also mentions the efficacy of immunotherapy being greater when a patient exhibits a large number of gene mutations due to DNA repair defects.

Naturally, to know whether or not it would be worthwhile to give a patient immunotherapy if there is still a lack of evidence for a specific cancer type, one would need to test the patient to understand the above expressions of proteins, gene mutations — these aspects of a cancer are very subjective and differ from person to person. However, genetic testing is not commonly offered.

Photo by Kendal on Unsplash

Going back to effectiveness: if the above conditions are met, then yes, immunotherapy is promising. While it would be wonderful to be able to cite a general statistic that would measure patients’ response rate to immunotherapy, there is no one magic number. Every cancer, targeted drug, and situation are different.

However, to provide some data, here is a concrete example of the response rate of soft-tissue sarcoma patients (undifferentiated pleomorphic sarcoma) to a checkpoint inhibitor (the same Pembrolizumab mentioned above). A multicenter phase 2 trial (SARC-028) showed an overall response rate of 40% (4/10) to the agent in patients with this diagnosis.

While 40% does not seem like a lot, in the cancer world it is a good result. For context, the chemo agents administered to sarcoma patients on average have a response rate of 10–30%.

What’s more is that the body has a miraculous ability to recover. That is, it can often respond to immunotherapy after all else has failed and the patient’s organism is ridden with toxicity from chemo.

The other benefits of immunotherapy involve longer remissions and comparatively low toxicity levels.

According to the Cancer Research Institute “immunotherapy can train the immune system to remember cancer cells” and how to respond to them. This may result in the cancer staying in remission longer (a year or more) than after chemo (weeks or months).

Given the outstanding results that immunotherapy has shown for specific cancer types, its comparatively low toxicity levels, and its ability to work with the body rather than against it, the conclusion that many in the medical community have come to is that it’s the most promising cancer treatment developed to date.

5. Why is immunotherapy so expensive?

If immunotherapy is effective, then the question of accessibility becomes even more important. Don’t we want to save as many lives as possible and eradicate cancer in the long term? It seems that this is the goal when you speak to medical professionals and watch fundraising campaigns of cancer research organizations.

But immunotherapy is the least bit affordable. The average checkpoint inhibitor therapy costs on average USD $100,000 a year. This number can easily soar to as much as USD $250,000, as immunotherapy is often given in tandem with chemotherapy drugs.

Source: Vox

Hagop Kantarjian, MD et. al, cite four main reasons why cancer drugs are priced so steeply:

(1)it costs $1 billion or more to take a drug to market, (2) prices are based on benefits to patients, (3) free market forces eventually settle prices at reasonable levels, and (4) controlling drug prices or allowing price-lowering competition can stifle innovation.

Based on the above rationale, it is clear that cancer drug prices follow their own economic logic that has nothing to do with the idea of what the market will bear. When a potentially life-saving drug costs twice or even three times the average household income and a person has to sell his/her assets to get it, this is not a fairly-priced commodity.

As for my Canadian readership, if you think that these drugs are accessible in Canada because of our public health care system, this is where you will be disappointed.

After being rejected for funding by the provincial government, our BC Cancer oncologist told us that our only option to access immunotherapy was to go private.

Yes, I was also surprised when I learned that private health care does exist in Canada outside of dentistry. But no, you will not find these clinics just by googling “immunotherapy clinics in Canada”. They’re a bit of a clandestine operation for those who can afford the exorbitantly priced treatment.

So it seems that accessing immunotherapy is and will continue to be a problem regardless whether you live in a country that has private or public health care.

The burden on the government to provide expensive treatment is as high as it is on an individual trying to cover the expense themselves. The only difference is that when you pay into a publically-funded health care, I believe you deserve to try the best treatment and have access to care that is continuously optimized. A little utopian, I know.

While I do not want to get too cospiriological, I cannot help but wonder if there is a darker side to this story? If there is a treatment out there that can keep people in remission and is made accessible to all, what will eventually happen to the pharmaceutical industry ?

After all, this is an industry that makes billions by being on a constant and exclusive hunt to come up with “the best next thing” — a treatment that will work just long enough until you suddenly need the next dose.