Cancer Immunotherapy: Immune Checkpoint Blockade Therapy

Releasing the Brakes on the Immune System

Note: This is just part 2 of my article series on cancer immunotherapy and covers the basics of what might be the earliest breakthrough in immunotherapies: immune checkpoint blockade therapy. It will require a basic understanding of the cellular mechanisms in the immune system.
If you don’t have prior exposure or understanding of how the immune system works, check out part 1 in the series where I go over the basics of the human immune system, and then come back to continue reading this article!

Photo by Alex King on Unsplash

As obvious as it may seem today, the concept that the immune system was capable of attacking cancer cells was widely ridiculed for the longest time. Experts used to firmly believe that there was no way for the immune system to actually recognize cancers since, unlike pathogens like viruses and bacteria, the cancer cells originated in our body, and therefore resembled our own cells. Only after determined, relentless work by several researchers in the later 20th century did this notion finally begin to unravel, laying the foundation for the use of immunotherapy in cancer treatment.

One discovery that came from this relentless research was the realization that the problem didn’t always lie in the inability of the immune system to detect cancer cells. In fact, in many patients, the immune system had recognized cancer cells and responded by sending armies of T-cells to attack them. But due to some interference with immune checkpoints, it was almost as if this army of T-cells ready for battle was told to stop right as it reached the enemy lines.

Immune Regulatory Mechanisms

As discussed in the previous article in this series, the immune system is unbelievably powerful at defending from pathogens and invaders. Without the versatility, adaptability, and complexity of the system, even the simplest and least harmful pathogens could be sufficient to overwhelm our bodies.

But this power comes with a possible side-effect. If the system was to become unleashed and dysfunctional, this same power could potentially be used against your own body, in the form of an autoimmune attack/disease. Autoimmune diseases affect up to 23.5 million Americans, with many of the diseases being fatal.

Rheumatoid arthritis is an autoimmune disorder that attacks the tissues of the joints, causing inflammation, swelling, pain, among many other severe symptoms. | Image from WebMD

In the case of T-cells (most relevant to cancer immunotherapy), two main mechanisms exist to ensure immune tolerance to one’s own body (in other words, to “self-antigens”). Central tolerance operates on T-cells during their development in the thymus via negative clonal selection (killing off self-reactive T-cells). However, for some types of T-cells, self reactivity is required for their function, leading to some level of positive selection for self-reactive T-cells in the thymus. In other cases, some self-reactive T-cells might be able to evade the negative clonal selection mechanisms. To ensure these self-reactive T-cells don’t harm the body, peripheral tolerance employs a variety of mechanisms to restrain autoreactivity, including the use of regulatory T-cells (discussed in the previous article on the function of the immune system).

However, due to the selective pressure exerted on the tumors by the immune system, immune tumor editing, which is essentially the evolution of stronger and more resistant cancer cells as a result of a fight with the immune system, sometimes gives rise to cancer cells that take advantage of these immunosuppressive mechanisms for their survival.

Cancer immune checkpoint blockade therapy, then, is the term to describe the oncotherapy that interferes with the expression of these suppressive mechanisms in patients suffering from cancer to essentially release the “off-switch” preventing activated T-cells from attacking tumors. In this article, I’ll discuss CTLA-4 and the PD-1/PD-L1 system, two well-studied suppressive pathways involved in such immunosuppressive mechanisms that have been successfully targeted in cancer immune blockade therapies with multiple FDA-approved medications.

CTLA-4

Cytotoxic T-cells (CD-28+) are responsible for finding dysfunctional or infected cells of the body by recognizing foreign target proteins presented on the MHC-I proteins with their T-cell receptor (TCR). In order to increase the strength of their response, however, the T-cells can also be co-stimulated by antigen-presenting cells (APCs) via binding of B7 ligands to the CD-28 receptor.

To regulate this response, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) acts as a competitor for the CD28 receptor. It binds to the same ligands, but does so with higher affinity and eagerness than the CD-28 receptor. However, unlike the CD-28 receptor, which initiates a signal cascade to further stimulate the T-cells, CTLA-4 produces no signal at all, or might even produce inhibitory signals. As such, a simple regulation pathway is formed by the competition between CD-28 and CTLA-4 to bind to the B7 ligands and stimulate or inhibit the T-cells, respectively.

This can also be done externally, mainly via regulatory T-cells. T-regs also display CTLA-4 receptors on their membrane, and can bind to the B7 ligands of the APCs. By doing so, they can prevent the CD-28 receptors of the cytotoxic T-cells binding to those ligands as well, reducing the strength of their response.

In general, higher levels of CTLA-4, whether before or after T-cell activation, prevents the cytotoxic T-cells from being able to attack and destroy tumors effectively. This makes the molecule a strong target for immune checkpoint blockade therapy in order to release the breaks that might decrease their efficacy at fighting cancer.

Ipilimumab is an example of a medication that uses artificial antibodies to target the CTLA-4 molecule and block its action in a variety of ways. The antibody’s binding epitope (sequence on antigen where an antibody binds) overlaps with the domain that interacts with the B7-ligands, suggesting that the main mechanism behind ipilimumab’s action to inhibit CTLA-4 is by preventing its competition with CD-28. This occurs mainly in the lymph nodes where APCs that may have run into tumor cells would attempt to activate the T-cell response. Overall, this greatly increases the magnitude of the anti-tumor response in patients with many different types of cancers, helping them fight and hopefully beat their condition. As of 2018, ipilimumab has been FDA-approved for different types of melanoma and renal cell carcinoma.

Action of Anti-CTLA-4 antibodies | National Cancer Institute

PD-1/PD-L1

The PD-1/PD-L1 regulatory system is involved in a negative feedback loop where increased T-cell activation stimulates the system, which in turn attenuates local T-cell responses. PD-1, expressed after activation of T-cells and B-cells, regulates T-cell activation by interacting with PD-L1 and PD-L2. These ligands are widely expressed in nonlymphoid tissue in the body, with increased expression in response to cytolytic and effector T-cell function. Upon activation of PD-1 by the ligands, an enzyme called SHP2 is activated, which inactivates the T-cell receptors to prevent activation of the immune response even when the antigen recognized by the T-cell receptor is found. The big difference between the action of PD-1 and CTLA-4 is that CTLA-4 resists initial activation of the T cells, but PD-1 actually stops the action of activated T cells at their target tissues.

In general, this serves to prevent autoimmune pathologies by bringing T-cells that might be reacting against self antigens or be overactivated under control. But cancer cells can take advantage of this system to prevent T-cell function against tumors. In some solid and blood tumors, PD-L1 is expressed on the membranes of the cancer cells, thereby stopping T-cell-mediated killing of the cancer cells by activating the inhibitory PD-1/PD-L1 regulatory system.

Therapeutically, this inhibition of T-cells is prevented either by targeting the PD-1 receptor, much like the drugs directed against CTLA-4, or by targeting the PD-L1 ligand expressed on cancer cells. Antibodies like Nivolumab and Pembrolizumab attach to the PD-1 receptors on T-cells to prevent their interaction with PD-L1. Meanwhile, antibodies like Avelumab and Durvalumab work very similarly but bind to the PD-L1 proteins expressed on cancer cells to prevent their detection by the T-cell PD-1 receptors.

Side Effects

So you might guess, releasing these brakes can also have significant side effects on the body. In many cases, there is risk of autoimmune conditions developing as the regulation of the immune system becomes weaker because of these drugs. Though most of these generally present themselves in the form of conditions like colitis (inflammation of the colon) that patients can recover from easily, in patients with pre-existing autoimmune pathologies, the results can be disastrous.

But, in general, these therapies have achieved great success in helping patients all around the world make remarkable recoveries, or at least allowed them to live a slightly longer and healthier life. Furthermore, immune checkpoint blockade therapy is only one of the first of a range of different immunotherapies targeting cancer, each being more powerful and effective than the last. And these other therapies are exactly what I’ll be discussing as I continue this series of articles on cancer immunotherapies, so stick around to find out more about brilliant innovations in the space that are saving hundreds if not thousands of lives around the world.

But that’s all from me for now! If you’re interested in finding out more about what I’m passionate about and what I’m working on, check out my website and follow me on Twitter. Also, to keep up with my growth and progress, make sure you subscribe to my newsletter here. See you next article!

If you’re interested in reading more about immunology-related topics, check out my article on the vaccine development process and why they take so long to make and my article on everything you need to know about the coronavirus.

18 y/o innovator working on reversing ageing and researching cancer vaccines. www.akshajdarbar.com