Sri Krishna, Arizona State University
Most of us know about the conventional treatment of cancer: surgery to remove tumors, chemotherapy and radiation. But within the last five years, a new class of drugs that use our immune systems to fight cancer are gaining traction in cancer treatment. This is called “immunotherapy.”
Instead of killing cancer cells with radiation or chemotherapy, immunotherapy mobilizes the immune system to fight against cancer much like it does against bacteria and viruses.
For a training immunologist like myself, immune therapies have opened new doors to understanding and treating cancers. In the future, immunotherapy could mean a personalized treatment, entirely tailored to an individual. As exciting as that sounds, we still have plenty of work to do, as there remains a lot we don’t know about the immune system. Here are some of the challenges we need to overcome to create these personalized treatments.
Challenge #1: Tumors don’t want the immune system to know they are tumors
In the late 1980s, researchers started to wonder if the immune system could fight tumors the same way it fought foreign invaders. Studies in mice and in humans showed that when immune cells were extracted from a body, reprogrammed and transferred back into the same body, they caused tumors to temporarily shrink, giving first indications of immunotherapy at work.
In turns out that tumors are pretty vicious in avoiding the immune system. In the 1990s, researchers discovered that tumors can actively put “brakes” on the body’s immune system to evade detection by T-cells, a special kind of immune cell. T-cells search for signs of infection within cells by looking for specific protein codes on the cell surface. When T-cells decide that protein codes displayed on a cell don’t look like they belong to normal cells, they attack these abnormal cells and kill them (as shown in this fantastic video).
Tumors can block T-cells from recognizing these protein codes. By doing this, tumors essentially go into stealth mode, flying under the radar of immune detection.
We’ve figured this challenge out – sort of. Extensive research on the T-cell brakes eventually led to drugs that block the effects of these brakes – allowing the immune system to detect and attack tumors that would otherwise be invisible to it – and present-day cancer immunotherapy was born.
Challenge #2: Immunotherapy drugs are highly effective, but not in everyone
Today there are three drugs approved as immune therapies – Ipilumimab, Nivolumab and Pembrolizumab. All three drugs act by releasing the T-cell brakes in different ways, freeing T-cells to look for the small protein codes characteristic of tumor cells.
These drugs have provided long-term remissions in patients with metastatic relapses in cancers such as melanoma and lung cancer. This means that patients whose cancers came back after an initial chemotherapy treatment (often a 3-month death sentence) remarkably survived, in some cases for several years, after their T-cells were rebooted to attack cancer. Very few conventional treatments can offer a comparable second chance after relapse.
But there is a problem: these drugs do not work for everyone. They are approved only to treat melanoma and certain types of lung cancer, and even in these cancers, these drugs only work in some patients. For instance, in about 20% of people with metastatic melanoma, Ipilimumab can double the long-term survival. For the other 80%, the drug is much less effective.
Scientists say that part of the reason why immunotherapy drugs can be amazingly effective in some patients, and much less effective is others, boils down to differences in our DNA.
Although we share 99.9% of our DNA with each other, there is massive variation from one individual to the next, partly because of our genetics and partly due to the environment. This variation extends to our tumors and our immune system. Because of this genetic variation that makes us who we are, our immune systems, and thus our cancers, have their own life story.
To try to solve this problem, researchers are trying to understand the genetic basis of clinical response to immunotherapies, and developing techniques to identify whether a patient who walks into the clinic with cancer will benefit from these drugs before going under treatment.
Challenge #3: Survival of the fittest tumors
In recent years we’ve learned that one of the reasons tumors are hard to treat is because they evolve. Some researchers believe that tumors exist only because they have evolved to hide from the immune system. This process takes years of natural selection, where only the fittest tumor cells, which effectively hide from or actively fight against the immune system, manage to survive, grow and cause major complications.
This means that we can expect that at least in some patients undergoing immune therapy, their tumors can evolve resistance to immune system detection and can come back. Although our immune system is capable of constantly evolving to counter viruses and bacteria, tumor evolution is a formidable enemy to overcome, and we are just beginning to understand this aspect of the disease.
Challenge #4: The immune system ‘blind spot’
Our immune system carries out a fine balancing act between hunting down and attacking cells that can harm us, such as viruses and bacteria, and leaving healthy “self” cells in our bodies (or good bacteria) alone. Immune cells that recognize our own normal “self” cells are killed off early during development, which prevents us from developing autoimmune disorders.
But most tumors result from our own cells. So how do we get the immune system to fight “self” cells it is supposed to ignore, and how do we make sure the immune system targets tumor cells, but not healthy cells? This is a big challenge for immune therapies.
By freeing T-cell brakes, current immunotherapies often work by overcoming these blind spots: immune cells suddenly start seeing our own “self” cells, which is very effective against tumors disguised as our own normal cells. The downside, however, is that this often upsets the delicate balance between autoimmunity and cancer.
As a result, some patients treated with immunotherapy experience autoimmune reactions.
Some melanoma patients undergoing immunotherapy have been known to develop Vitiligo, a condition where that leads to the loss of skin color. Other patients undergoing treatment also report gastrointestinal distress as a common side effect from the immune system being overactivated. In extreme cases, severe life-threatening autoimmune reactions such as organ rejection can happen, indicating that immunotherapy drugs need careful examination and regulation.
Overcoming the challenges
Researchers are starting to sequence the DNA of tumors to get a better understanding of how they work at the genetic level. We have just begun to understand how different they are from other cells of our body.
Tumor DNA sequencing, along with emerging technologies, like liquid biopsies on the blood to diagnose and monitor tumors, will help us understand how cancers evade the immune system and who will actually benefit from these treatments. In patients who do not respond to regular immunotherapies, it has been proposed that immunotherapies might be combined with conventional chemotherapies (“immunochemotherapy”) to improve potency of treatment.
We are also at the beginning of personalized immune therapies. This treatment involves designing vaccines made of engineered immune cells from a patient’s own body, to treat their own tumors. In the not too distant future, a patient may walk into a clinic, have their tumors sequenced and their immune system analyzed to decide on the best course of personalized immune therapy.
For now, though, we have to be careful in regulating immune therapies, and get better at understanding the intricate dance between cancers and our immune systems.
[hr] Sri Krishna is PhD Candidate, Biological Design, School of Biological and Health Systems Engineering at Arizona State University.