Immunotherapy 101: What It Is and How It Works

How Immunotherapy Can Help Our Immune Systems Fight Cancer

Immunotherapy injection
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If you're feeling confused about exactly how immunotherapy works to treat cancer, there's a good reason. Immunotherapy isn't just one type of treatment; rather there are several widely varying types of treatments which fall under this heading. The commonality is that these treatments either use the immune system, or the principles of the immune response, to fight off cancer. In other words, these treatments, referred to as biologic therapy, are used to either alter the body's immune system or use substances made by the immune system to fight cancer.

Why Is Immunotherapy So Exciting?

If you've read a newspaper recently, you've probably seen headlines with dramatic messages such as "the cure is near" when describing immunotherapy. Is this something to become excited about, or is it just more media hype?

Immunotherapy was named the 2016 clinical cancer advance of the year by the American Society of Clinical Oncology. For those living with cancer, this field, along with advances in treatments such as targeted therapies, are reasons to feel a sense of hope—not just for the future, but for today.

Unlike many advances in oncology which build upon earlier treatments, immunotherapy is mostly an entirely new way to treat cancer (non-specific immune modulators such as interferon have been around a few decades). Compared to many other treatments:

  • Some of these treatments may work across cancer types (in other words, a drug could work for, say, melanoma and lung cancer). 
  • Some of these treatments may work for the most advanced and hardest to treat cancers (for example, they may be effective for cancers such as advanced stage lung cancer or pancreatic cancer).
  • In some cases, the results are lasting—what oncologists refer to as a "durable response." Most cancer treatments for solid tumors, such as chemotherapy and drugs which target specific genetic changes in cancer cells, are limited; cancer cells eventually become resistant to the treatment. While nobody dares to whisper the word "cure" yet, there is hope that for a minority of people with some types of cancers—these medications may offer the opportunity for long-term control of their cancer. 

History of Immunotherapy

The concept of immunotherapy has actually been around for a long time. A century ago, a physician known as William Coley noted that some patients, when infected with a bacteria, appeared to fight off their cancers. Another physician named Steven Rosenberg is credited with asking questions about a different phenomenon with cancer. On rare occasions, cancer may just go away without any treatment. This spontaneous remission or regression of cancer has been documented, although it is a very rare occurrence. Dr. Rosenberg's theory was that his patient's immune system had attacked and cleared the cancer. 

Theory Behind Immunotherapy

The theory behind immunotherapy is that our immune systems already know how to fight cancer. Just as our bodies are able to identify, label, and mount an immune response against bacteria and viruses which invade our bodies, cancer cells may also be tagged as abnormal and eliminated by the immune system.

Then Why Don't Our Immune Systems Fight Off All Cancers?

Our immune systems do work tremendously well in the process of cleaning up damaged cells that could eventually become cancer cells. We have several genes built into our DNA, known as tumor suppressor genes, which provide the blueprint for proteins that repair and rid the body of cells that have been damaged. Perhaps a better question might be, "Why don't we all develop cancer more frequently?"

Nobody knows exactly why some cancer cells escape detection and destruction by the immune system. Part of the reason, it's thought, is that cancer cells can be harder to detect than bacteria or viruses because they arise from cells that are considered normal by our immune system. Immune cells are designed to categorize what they see as self or non-self, and since cancer cells arise from normal cells in our bodies, they may slip by as normal. The sheer volume of cancerous cells may also play a role, with the number of cancer cells in a tumor overpowering the ability of the smaller number of immune cells. 

But the reason is probably trickier than recognition or numbers—or at least, cancer cells are trickier. Often cancer cells evade the immune system by "pretending" to look like normal cells. Some cancer cells have figured out ways to disguise themselves, to put on a mask if you will. By hiding in this way they can then escape detection. In fact, one type of immunotherapy drug works by essentially removing the mask from tumor cells. 

As a final note, it's important to note that the immune system has a fine balance of checks and balances. On one side it's important to fight off foreign invaders. On the other side, we don't want to fight off cells in our own bodies, and in fact, autoimmune diseases such as rheumatoid arthritis are related to an "overactive immune system."

Limitations of Immunotherapy

As you read on, it's important to recognize some of the limitations of immunotherapy at this stage of development. One oncologist referred to it this way: Immunotherapy is to cancer treatment as the Wright Brothers first flight was to aviation. The field of immunotherapy is in its infancy.

We know that these treatments do not work for everyone, or even for the majority of people with most cancers. In addition, we don't have a clear indication of who exactly will benefit from these drugs. The search for biomarkers, or other ways of answering this question, is an active area of research at this time.

A Brief Review of the Immune System and Cancer

To understand a little about how these individual treatments work, it can be helpful to briefly review how the immune system functions to fight cancer. Our immune system is made up of white blood cells as well as tissues of the lymphatic system such as lymph nodes. While there are many different types of cells as well as molecular pathways that result in the removal of cancer cells, the "big guns" in fighting cancer are T-cells (T lymphocytes) and natural killer cells. This complete guide to understanding the immune system provides an in-depth discussion of the basics of the immune response.

How Does the Immune System Fight Cancer?

In order to fight off cancer cells, there are many functions our immune systems need to perform. Simplistically, these include:

  • Surveillance: The immune system first needs to find and identify cancer cells. Our immune cells need to both check out all cells in their midst and be able to recognize cancer cells as being non-self. An analogy would be a forestry worker walking through the forest looking for diseased trees.
  • Tagging: Once discovered, our immune system needs to mark or label cancer cells for destruction. Following the analogy, the forestry worker would then need to tag or label the diseased trees with orange spray paint.
  • Signaling: Once cancer cells are marked, our immune cells need to sound an alarm, attracting the immune cells that fight cancer to the region where it's found. Continuing the analogy, the forestry worker would have to return to his office and phone, text, and email a tree service to come and remove the diseased trees.
  • Fighting: Once cancer cells are recognized and marked, and immune cells have responded to the alarm and migrated to the site, cytotoxic T cells and natural killer cells attack and remove cancer cells from the body. Finally, in the analogy, the tree service workers would cut down and remove the diseased trees.

How Do Cancer Cells Hide From the Immune System?

It can also be helpful to know how cancer cells often manage to evade detection or attack by our immune systems. Cancer cells may hide by:

  • Decreasing the expression of antigens on the surface of the cells. This would be analogous to the trees removing signs of their disease from their branches or leaves.
  • Expressing substances on the surface of the cell which inactivate the immune system. Cancer cells may produce molecules which depress the immune response. In analogy, the trees would do something to chase off the forestry workers and tree service.
  • Cancer cells may also cause nearby non-cancer cells to secrete substances that reduce the effectiveness of the immune system. This approach is referred to as altering the microenvironment, the area surrounding the cancer cells. Stretching the analogy a bit, the diseased trees would enlist the ferns and lilacs to join in to help keep the forestry workers away.

Types and Mechanisms of Immunotherapy

You may have heard immunotherapy described as a treatment which "boosts" the immune system. These treatments are actually much more complex than simply giving the immune system a boost. Let's take a look at some of the mechanisms by which immunotherapy works, as well as categories of treatments being used or studied today.

Mechanisms of Immunotherapy

Some mechanisms by which immunotherapy medications can treat cancer include:

  • Helping the immune system recognize cancer
  • Activating and amplifying immune cells 
  • Interfering with a cancer cell's ability to hide (de-masking)
  • Interfering with the microenvironment of cancer cells by altering cancer cell signals
  • Using the principles of our immune system as a template for designing cancer drugs

Types of Immunotherapy

Immunotherapy methods currently approved or being evaluated in clinical trials include:

  • Monoclonal antibodies
  • Checkpoint inhibitors
  • Cancer vaccines
  • Adoptive cell therapies such as CAR T-cell therapy
  • Oncolytic viruses
  • Cytokines
  • Adjuvant immunotherapy

It's important to note that there is significant overlap between these therapies. For example, a medication used as a checkpoint inhibitor may also be a monoclonal antibody. 

Monoclonal Antibodies (Therapeutic Antibodies)

Monoclonal antibodies work by making cancer cells a target and have been used for some time, especially for cancers such as some types of lymphoma.

When our immune systems come into contact with bacteria and viruses, messages are sent which result in the formation of antibodies. Then, if the same invader shows up again, the body is prepared. Immunizations such as the flu shot work by showing the immune system a killed flu virus (the shot) or an inactivated flu virus (the nasal spray) so it can produce antibodies and be prepared if a live flu virus enters your body.

Therapeutic or monoclonal antibodies work in a similar way but instead these are "manmade" antibodies designed to attack cancer cells rather than microorganisms. Antibodies attach to antigens (protein markers) on the surface of cancer cells, like a key would fit into a lock. Once the cancer cells are thus marked or tagged, other cells in the immune system are alerted to destroy the cell. You can think of monoclonal antibodies as similar to the orange spray paint you might see on a diseased tree. The label is a signal that a cell (or a tree) should be removed. 

Another type of monoclonal antibody may instead attach to an antigen on a cancer cell in order to block a growth signal from gaining access. In this case, it would be like putting a key in a lock, so that another key—a growth signal—could not connect. The medications Erbitux (cetuximab) and Vectibix (panitumumab) work by combining with and inhibiting the EFGR receptor (an antigen) on cancer cells. Since the EGFR receptor is thus "blocked" the growth signal cannot attach and tell the cancer cell to divide and grow.

A widely used monoclonal antibody is the lymphoma medication Rituxan (rituximab). These antibodies bind to an antigen called CD20—a tumor marker found on the surface of cancerous B lymphocytes in some B cell lymphomas.

Monoclonal antibodies are currently approved for several cancers. Examples include:

  • Avastin (bevacizumab)
  • Herceptin (trastuzumab)
  • Rituxan (rituximab)
  • Vectibix (panitumumab)
  • Erbitux (cetuximab)
  • Gazyva (obinutuzumab)

Another type of monoclonal antibody is a bispecific antibody. These antibodies bind to two different antigens. One tags the cancer cell and the other works to recruit a T cell and bring the two together. An example is Blincyto (blinatumomab).

Conjugated Monoclonal Antibodies 

The monoclonal antibodies above work alone, but antibodies may also be attached to a chemotherapy drug, toxic substance, or a radioactive particle in a treatment method called conjugated monoclonal antibodies. The word conjugated means "attached." In this situation, a "payload" is delivered directly to a cancer cell. By having an antibody attach to an antigen on a cancer cell and deliver the "poison" (drug, toxin, or radioactive particle) directly to the source, there can be less damage to healthy tissues. Some medication in this category approved by the FDA include:

  • Kadcyla (ado-trastuzumab): a monoclonal antibody attached to a chemotherapy drug for the treatment of breast cancer
  • Adcetris (brentuximab vedotin): attached to a chemotherapy drug
  • Zevalin (ibritumomab tiuxetan): attached to a radioactive particle
  • Ontak (denileukin difitox): a drug that combines a monoclonal antibody with a toxin from the bacteria that causes diphtheria

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors work by taking the brakes off the immune system.

As noted above, the immune system has checks and balances so that it doesn't overperform or underperform. In order to keep it from overperforming—and causing autoimmune disease—there are inhibitory checkpoints along the immune pathway that are regulated, just as brakes are used to slow down or stop a car.

As noted above, cancer cells can be tricky and deceive the immune system. One way they do this is via checkpoint proteins. Checkpoint proteins are substances which are used to suppress or slow down the immune system. Since cancer cells arise from normal cells, they have the ability to make these proteins but use them in an abnormal way to escape detection by the immune system. PD-L1 and CTLA4 are checkpoint proteins that are expressed in greater number on the surface of some cancer cells. In other words, some cancer cells find a way to use these "normal proteins" in an abnormal way. In turn, these proteins put a lead foot on the brakes of the immune system.

Medications called checkpoint inhibitors can bind with these checkpoint proteins such as PD-L1, essentially releasing the brakes, so the immune system can get back to work and fight off the cancer cells.

Examples of checkpoint inhibitors currently being used include:

  • Opdivo (nivolumab)
  • Keytruda (pembrolizumab)
  • Yervoy (ipilimumab) 

Research is now looking into the benefits of combining two or more drugs in this category. For example, using PD-1 and CTLA-4 inhibitors together (Opdivo and Yervoy) is showing promise.

Adoptive Cell Transfer and CAR T-cell Therapy

Adoptive cell and CAR T-cell therapies are immunotherapy methods which enhance our own immune systems. Simplistically, they turn our cancer-fighting cells into better fighters by increasing either their fighting ability or their numbers.

Adoptive Cell Transfer

As noted earlier, one of the reasons our immune systems don't fight off large tumors is that they are simply overpowered and outnumbered. Think of having 10 soldiers on the front lines going against 100,000 opponents (cancer cells). These treatments take advantage of the fighting action of the soldiers but add more soldiers to the front line.

With these treatments, doctors first remove your T cells from the region surrounding your tumor. Once your T cells are collected, they are grown in the lab (and activated with cytokines). After they are sufficiently multiplied, they are then injected back into your body. This treatment has actually resulted in a cure for some people with melanoma.

CAR T-cell Therapy

Continuing with the automobile analogy from above, CAR T-cell therapy may be thought of as an immune system "tune up." CAR stands for chimeric antigen receptor. Chimeric is a term that means "joined together." In this therapy, an antibody is joined together with (attached to) a T-cell receptor. 

As with adoptive cell transfer, T-cells from the region of your tumor are first collected. Your own T-cells are then modified to express a protein referred to as chimeric antigen receptor or CAR. This receptor on your T-cells allows them to attach to receptors on the surface of cancer cells to destroy them. In other words, it assists your T-cells in recognizing the cancer cells.

There are not yet any CAR T-cell therapies that are approved, but they are being tested in clinical trials with encouraging results, especially against leukemia and melanoma.

Cancer Treatment Vaccines

Cancer vaccines are immunizations which work essentially by jumpstarting the immune response to cancer. You may hear of vaccines which can help prevent cancer, such as hepatitis B and HPV, but cancer treatment vaccines are used with a different goal—to attack a cancer already present.

When you are immunized against, say, tetanus, your immune system is exposed to a small amount of killed tetanus. In seeing this, your body recognizes it as foreign, introduces it to a B-cell (B-lymphocyte) which then produces antibodies. If you are again exposed to tetanus, like if you step on a rusty nail, your immune system is primed and ready to attack.

There are a few ways in which these vaccines are produced. Cancer vaccines may be made using either tumor cells, or substances produced by tumor cells.

An example of a cancer treatment vaccine used in the United States is Provenge (sipuleucel-T) for prostate cancer. Cancer vaccines are currently be tested for several cancers, as well as to prevent recurrence of breast cancer.

With lung cancer, two separate vaccines—CIMAvax EGF and Vaxira (racotumomab-alum)—have been studied in Cuba for non-small cell lung cancer. These vaccines, which have been found to increase progression-free survival in some people with non-small cell lung cancer, are beginning to be studied in the United States as well. These vaccines work by getting the immune system to make antibodies against epidermal growth factor receptors (EGFR). EGFR is a protein on the surface of cells that is overexpressed in some people with lung cancer.

Oncolytic Viruses

The use of oncolytic viruses has been referred to analogously as "dynamite for cancer cells." When we think of viruses, we usually think of something bad. Viruses such as the common cold infect our cells by entering the cells, multiplying, and eventually causing the cells to burst.

Oncolytic viruses are used to "infect" cancer cells. These treatments appear to work in a few ways. They enter the cancer cell, multiply and cause the cell to burst, but they also release antigens into the bloodstream which attracts more immune cells to come and attack.

Talimogene laherparepvec (T-VEC, or Imlygic) is the first FDA-approved oncolytic virus. This virus can attack both cancer and normal cells, but unlike the cancer cells, the normal cells are capable of fighting back.

Cytokines (Immune System Modulators)

Immune system modulators are a form of immunotherapy that has been available for many years. These treatments are referred to as "non-specific immunotherapy." In other words, they work to help the immune system fight off any invader, including cancer. These immunoregulatory substances—cytokines—including both interleukins (ILs) and interferons (IFNs) accentuate the ability of immune cells to fight cancer.

Examples include IL-2 and IFN-alpha which are used for kidney cancer and melanomas among other cancers.

Adjuvant Immunotherapy

The Bacillus Calmette-Guerin (BCG) vaccine is one form of adjuvant immunotherapy that is currently approved for treating cancer. It's used in some parts of the world as protection against tuberculosis. It may also be used to treat bladder cancer. The vaccine, instead of being given as an immunization, is instead injected into the bladder. In the bladder, the vaccine produces a nonspecific response which helps to fight the cancer.

Side Effects

One of the hopes has been, because immunotherapy addresses cancer specifically, that these treatments will have fewer side effects than traditional chemotherapy drugs. Like all cancer therapies, however, immunotherapy medications can result in adverse reactions, which vary depending on the category of immunotherapy as well as the particular medications. In fact, one of the ways that these effects are described is "anything with an itis"—"itis" being the suffix meaning inflammation.

The Future 

The field of immunotherapy is exciting, yet we have much to learn. Thankfully, the amount of time it is taking for these new treatments to actually be used for people with cancer is also improving, whereas in the past there was a lengthy period of time between discovery of a drug and the time it was used clinically. With medications such as these, in which drugs are developed looking at specific issues in cancer treatment, that development time is often significantly shorter.

As such, the use of clinical trials is also changing. In the past, phase 1 trials—the first trials in which a new drug is tested on humans—were considered more of a "last-ditch" effort. They were designed more as a method of improving medical care for those in the future rather than the person participating in the trial. Now these same trials may offer some people the only opportunity available to live with their disease.

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