by Alyssa Vito
Traditional cancer therapies (such as chemotherapy and radiation therapy) have shown widespread success against various cancer types, but are known to have toxic, undesirable side effects as they do not selectively kill cancer cells and therefore actively damage healthy cells as well. This is where immunotherapy comes into play. Immunotherapy is a form of therapy that uses the body’s own immune system to fight the cancer within it. Think of your body as a battlefield and your immune system the frontline of soldiers, ready to attack foreign invaders. The problem with cancer cells is that they are not easily recognized as foreign pathogens (such as viruses or bacteria) because they originate in the host’s body and mutate from normal cells. It has long been postulated that the immune system could be used to target and kill cancer cells, but the process of figuring out how to harness this ability is not a simple task.
The Immune System
The cells of the immune system are continually monitoring our tissues and patrolling the body for foreign invaders. There are many different types of immune cells that make up the complex immune response that keeps our body healthy. When a tumor is formed, the immune system reacts in a systemic manner. First, natural killer (NK) cells send stress signals when they detect damaged and cancerous cells. Dendritic cells (DCs) are then responsible for informing and activating other immune cells, such as cytotoxic T cells. Once activated, cytotoxic T cells act as border patrol agents, checking the antigens of every cell that passes by them. In this analogy, we can think of the antigens as passports. The cytotoxic T cells can sense that antigens on the tumor cells are “foreign” and “do not have the right passport”. These cells are then signaled for destruction and the cytotoxic T cells and NK cells release proteins, which punch holes in the surface of the tumor cells causing them to die through a process called apoptosis.
As the tumor evolves, genetic changes occur that give some tumor cells a survival advantage over others. This results in what we call a “heterogenous tumor”, meaning it is composed of multiple different types of tumor cells, each subtype having its own “passport” to identify it. While some cells may still be flagged as having the “wrong” passport and be killed by the immune system, others will mutate and evolve to no longer express the antigen that is sensed as being wrong by the killer immune cells. These cells are the driving force behind tumor persistence, and they evade immune-mediated killing with “fake passports”. As the immune system continues to work and kill the cells it can recognize, the cells it can’t sense become more prevalent and begin to form a tumor that goes fully undetected by the immune system.
Another trick of cancer cells is to actively supress cytotoxic T cells by expressing inhibitory molecules such as programmed death-ligand 1 (PD-L1). PD-L1 binds to the PD-1 receptor on T cells and deactivates them, stopping them from killing tumor cells. This is what we call an immune checkpoint. Tumor cells can also attract immune cells that supress the activity of other immune cells, in turn actually supporting tumor growth.
Checkpoint Blockade Therapy
There are various types of immunotherapies coming down the clinical pipeline. Some common ones that you may have heard of include adoptive cell transfer (ACT), chimeric antigen receptor (CAR) T-cell therapy, checkpoint blockade therapy and oncolytic virotherapy. While some immunotherapies focus on enhancing and/or expanding the patient’s own T cells to target the cancer cells, others focus on stopping T cell inhibitory pathways such as PD-L1.
Since the discovery of the PD-1/PD-L1 pathway by Dr. Tasuku Honjo in 1992, scientists have extensively studied checkpoints and the use of blocking antibodies to inhibit them. To show just how notable this discovery was to the field of oncology, Dr. Honjo was awarded the Nobel Prize for this finding in 2018. The award was shared with Dr. James Allison, who similarly uncovered the checkpoint pathway cytotoxic T-lymphocyte-associated protein 4, or CTLA-4. Antibodies that bind to either PD-1, PD-L1 or CTLA-4 have been used significantly in numerous clinical trials and with widespread success for many forms of cancer.
Unfortunately, not all patients will respond to these immunotherapies and some responses will be delayed or incomplete. One of the reasons for these differences in responses is that even patients with the exact same cancer, will still have individual expression levels of things such as PD-L1. As you can imagine, a patient whose cancer has higher expression of PD-L1, will inevitably benefit more from anti-PD-L1 therapy. Though personalized cancer therapy is still in its infancy and we do not yet understand how to scale it up within reasonable time and financial constraints, the field of oncology is moving towards a point in which we will be able to fully dissect the immune markers for every single patient and then design personalized therapeutic regimens based on that immune environment unique to their cancer.
Breast Cancer Immunotherapy
Immunotherapy for breast cancer got off to a slow start. This is primarily because most breast lesions have low levels of immune cells and low expression of markers such as PD-L1. Additionally, breast cancers that are positive for the overexpression of hormonal biomarkers (such as the estrogen receptor or progesterone receptor) already have good targeted therapies available to them. Where we have seen the strongest emergence of immunotherapy for breast cancer is for the aggressive subtype, triple negative breast cancer (TNBC), which has been shown to express higher levels of PD-L1, when compared to other breast cancer subtypes. For this reason, we have begun to see improved clinical outcome in TNBC patients treated with checkpoint blockade antibodies targeting the PD-1/PD-L1 pathway. It is however worth noting that in most breast cancer cases, this immunotherapy is still given in combination with chemotherapy or radiation therapy, which leads to a better response in some patients.
Will Immunotherapy Replace Current Treatments?
As scientists continue to explore ways of manipulating and enhancing the body’s natural immune response, we see more immunotherapies emerging in both preclinical and clinical studies. For the time being, immunotherapies often need to be supplemented with additional standard therapies. However, given the favourable outcomes we have seen and the limited toxicity to the patients, it is plausible that in the future we will see immunotherapies as the sole, first-line treatment for many types of cancer.
Though most breast cancers are well managed by current treatments (surgery, chemotherapy and radiation therapy), patients endure aggressive, invasive procedures that result in any number of side effects including but not limited to infertility, nausea, hair loss and muscle atrophy. I myself can speak to these devastating side effects as I was only 23 years old when diagnosed with stage II TNBC. As a subtype of the disease classified as being inherently aggressive and with no clear hormonal targets for therapy, TNBC patients are often subject to an extremely intense treatment regimen. I had a partial mastectomy, 8 rounds of dose-dense chemotherapy and 33 radiation therapy treatments. While I can say that these therapies undoubtedly saved my life, I can also say that I will forever live with the long-term side effects they inflicted upon my body.
As a researcher in the field of immunotherapy I am excited and optimistic about the future of cancer therapy. Scientists around the world are studying the immune system in such minute detail that we are constantly uncovering new functions and possible areas for intervention in the complex innerworkings of the body. Like most researchers, I shy away from using terms such as “cure” when talking about the future of cancer research. I do not believe that there will be a singular “cure” for cancer. That being said, it becomes more evident every day that it is instead reasonable to think about a future where cancer can become a “manageable” disease. And that is exciting to me.