The future of cell therapy
Why chimeric antigen receptor (CAR) technology is the next step towards immune system 2.0
Body under constant attack
At every single moment of your life, some cells in your body are invaded by a virus forcing it to produce more viral particles, or taken hostage by a parasite or bacteria or fungi, or just decide to screw it all and become neoplastic (pre-cancerous). While the attacks are constant and numerous, we usually do not stop our daily business to think about them. Truth be told, we do not really care about the small everyday challenges of living on a molecular level, we mostly care about the big picture, the sum of events that determine if our body is healthy or not.
In contrast, as scientists, part of our daily business is thinking about things, while our actions are mostly motivated by wonder and curiosity. Usually, this would lead us to wasting hours pondering things like:
“How the actual f*** does my body manage to keep an average of 37 trillion individual cells in check, when at the same time my brain fails to come up with a solution to keep my 2 cats from destroying the apartment?”
Surely, there must be something unique going on inside us that prevents our cells from running amok, right?
Well, not really. Our cells are evolutionary programmed to stick to a set of rules, similar to how we, as individuals in a society, have to stick to a set of laws. Unfortunately, the similarities do not stop here. Not unlike humans, even the most well-groomed cell, given the wrong circumstances, might end up making some wrong decisions, leading it to breaking these laws.
Most of the time, at least for cells, it is to no fault of their own, for example when their program gets corrupted by viruses, or when they get repeatedly damaged by radiation. In these cases, cells can become harmful for their surroundings. In these circumstances, cells regularly obey their pro-social “code of honor” and rather suicide than to inflict more harm to their neighbours, if they are still functional enough to make that decision.
Yet, occasionally it happens, that some cells, like humans, break loose from society and get ready to wreak havoc. This is exactly when we need law enforcement to protect the collective from the individual.
Luckily, our body has its own law enforcement; “the immune system”.
A hero in disguise, our immune system consists of many different cells performing different functions, similar to how law enforcement has anything from the police officer controlling traffic to the detectives solving crimes to anti-terror units and bomb-defusing robots and the military, as a last measure.
So to summarize, our body uses the executive power of our immune system to constantly guard what we call “us”, a macro-society of 37 trillion cells, against falling into disarray. A challenge unmatched in complexity by any other system in nature. Without our immune system, survival would have been impossible, and even today, in the era of modern medicine and antibiotics, we still heavily rely on it to live and thrive.
If our immune system is really that great, why would it cause severe allergic reactions to harmess things but ignore malignant cancer cells?
The vertebrate immune system evolved over millions of years and is insanely well equipped to deal with what apes and later humans would be exposed to throughout their lifetime. Mostly deadly bacteria and virus/parasites infection. However, in the last few thousand years, countless significant changes to our civilization and lifestyle completely altered our environment. In the past, an aggressive immune system would mean that your chances of survival were higher, thus it would have been selected for and passed down to the offspring. Today, hygiene standards dramatically improved and our immune system has it way easier; unfortunately, for some people, their immune system is still constantly looking for war.
An overactive immune system is like letting the army fight traffic jams, there is bound to be some nasty side effects.
At least that’s one of the explanations why allergic reactions are on the rise, but there might be more to this story, we are not completely sure yet. Don’t get me wrong, there is no question that life is still way better today than it ever was in the past. Life expectancy at least doubled since the development of antibiotics and hygiene standards, and infant or birth-related death rates are extremely reduced. What this shows is an important fact of today’s reality:
Nature (=evolutionary genetic adaptation) is too slow to keep up with our quickly changing environment.
To put it differently, age-related diseases like Alzheimer’s or cancer are byproducts of increased life span; nature never found it necessary to evolve rigorous protection against them, as it never planned for the human species to live as long as we do nowadays.
A quick note to “natural selection”; it is all about the survival of the offspring, never the parents. What this means is that Darwinian selection only made us survive as long as necessary to produce and raise offspring which can reproduce again, everything extra lifespan is just a bonus. Maybe this is a reason why for example elephants rarely get cancer, they had to evolve better genetic protection against cancer to gain enough time to reach sexual maturity, birth offspring and raise it to sexual maturity, a process which easily takes more than a quarter of a century.
In summary, we have to understand that while our immune systems’ potential for body defense is amazing, it is still running on the 1.0 software version, created at a time before we even discovered fire.
And this is where the story could have ended, if it wasn’t for human ingenuity.
“Welcome to the future, which disease can we cure for you today?”
Maybe this trashy slogan will be welcoming you very soon at your hospital of choice.
We have concluded that our immune system, while amazing, is in dire need of a software update, largely because it has to face a world today that is completely different from the world it evolved against in the past.
However, when it comes to the “how”, the situation gets immediately complex. If you remember the video above, our immune system has so many components with too many different functions, and if you screw with this delicate balance you might destroy the whole. Ideally, what we want is not to change how the immune system works, but rather teach it a few tricks how to handle the challenges of our modern world.
This sounds futuristic? Well, you might be pleasantly surprised to know that we have been doing this since the end of the 19th century, with a process called vaccination.
Next to antibiotics, vaccination is the single most important medical breakthrough ever invented to save lives.
One cannot stress enough the importance and impact of vaccination.
Take smallpox, a disease so devastating it killed an estimated 400,000 Europeans annually during the closing years of the 18th century and was responsible for a third of all blindness. It is estimated that 300–500 million people died of it in the 20th century alone, before vaccination initiatives eradicated it in 1979.
It is important to understand and appreciate vaccination, because unfortunately, vaccination is under attack today. Fraudulent claims and misinformation campaigns are on the rise and getting disproportional attention. The false notion that “vaccination is causing autism and should be avoided” is absurd and going against every piece of scientific evidence, against experienced history and ultimately against the value of human life.
The following is clear:
Vaccination is the first milestone in the quest for immune system 2.0
The principle of vaccination is quite simple to understand; scientists take the disease-causing agent (virus/bacteria) from the wild and then either extremely weaken or kill it in the laboratory, before administering the remains to the patient.
In doing this, our immune system learns to recognize and fight the invader, but in a training scenario we created, where the whole body is never exposed to real danger. Imagine having to fly an airplane without simulator training, this would be the equivalent challenge our immune system faces with pathogens of our modern world.
I think everyone can agree that it is reasonable to first teach our immune system how to fly, before we board a plane and put it in the pilots’ seat.
The development of wide-spread vaccination was amongst the biggest achievements of medicine in the past century. Once again, however, our environment has significantly changed by being exposed to industrial and post-industrial life styles (pollution, smoking, high-fat diets, exposure to fossil fuel remnants, artificial chemicals and the list goes on). Our cultural lives changed so much, that infectious diseases as the main cause of death all throughout human history was replaced by cardiovascular diseases and cancer. Again, it is not that cancer got way more common, but the eradication of infectious diseases as cause of death led people to live way longer, giving us more time to get hit by cancer or heart failure when we are old.
Today, 1 out 2 humans are at risk of developing or dying from cancer in their lifetime. We know now that what we understood as “cancer”, is more than just one single disease, it describes more than 400 different pathologies. Like viruses or bacteria, many cancers differ quite significantly from one another. With viruses, we needed to find different vaccines to teach our immune system to respond accordingly, measles are not polio, and polio has nothing to do with smallpox. For cancer, this understanding was missing until technologies like genome sequencing allowed us to look into different cancer cells to find out how quite different they actually are.
Historically, most of the research in cancer therapy is focused on characterizing molecular mechanisms of how different cancers behave and big pharma companies are screening millions of potential drug targets in the hope to find the one compound that can beat specific types of cancer. While chemotherapy overall has succeeded with treating certain cancers, it has too many side effects on healthy tissue and relapse occurs frequently, as well as drug resistance. For some cancers, like pancreatic adenocarcinoma, the field has not moved at all, with survival rates as bad as in the 1980s. It becomes increasingly clear, that in order to beat cancer, we will need to develop a treatment strategy that has the necessary complexity and precision to fight cancer cells while leaving the rest of the body (mostly) unharmed.
Faced with these limitations, scientists were driven to ask a simple question:
Can we maybe teach our immune system to attack cancer?
Which brings us to today, as the first seeds of those efforts finally bear fruit.
Chimeric Antigen Receptor (CAR) technology
The first CAR T-cells were developed at the Weizmann Institute of Science in Israel in the late 1980s by chemist and immunologist Zelig Eshhar, originally to target melanoma. The reason it took more than 2 decades to reach its current success has to do with many barriers that scientists had to break down; these problems included a tumor’s ability to escape immune recognition and the generally immunosuppressive tumor microenvironment, as well as finding ways to empower modified T-cells to proliferate and activate other immune cells.
So how does it work?
If you have watched the video above, you learned that our immune system uses specific proteins called “antibodies” to recognize and bind “antigens” of whatever they want to attack. Imagine antibodies as smartphone covers and antigens as smartphones. Every cover fits perfectly to only one phone, so you can find the right phone out of many others by just iteratively trying to put phones into a specific cover until finally one fits.
This “scaffold-fitting” is one of the basic principle of interactions between our cells.
Sometimes, you can have multiple covers (=antibodies) designed to fit one phone (=antigen), but no phone will naturally fit different covers designed for other phones.
Every cells’ surface is covered with thousands of different proteins, whose composition depends on the specific type of cell. Our immune system usually samples the surface proteins of invaders (e.g. bacteria or viruses), then takes a piece of those proteins and uses that piece (=antigen) to design custom-made antibodies which scaffold it. Subsequently, it loads up millions of “T-cells” with this specific antibody, which will allow the T-cells to find and attack the right “bad-actor” cell amongst trillions of harmless “civilian” cells.
During vaccination, our immune system goes through exactly this process:
- it probes the invader (bacteria, virus, parasite; artificial vaccine)
- chops him up to get some pieces of him (antigens)
- transports the remains of it to the lymph nodes (where most of our immune system is housed)
- designs specific custom-made antibodies against invader
- catalogues the antibody design plan (memory B cells)
- equips an army of T-cells with these specific antibodies to recognize their enemy.
That is some serious strategic work, called adaptive immunity
With CAR technology, scientists tried to jump in the middle of this strategizing process by modifying the sensors (=receptors) of T-cells to target what we tell them to.
The premise is simple: extract a patient’s T cells from blood and train them to recognize and kill cancer by modifying them to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen — The scientist.com
To reach this point, significant advances in immunology, gene delivery techniques, biotechnology, synthetic biology and even genome editing had to be made to finally make it feasible.
Technically, all CAR designs share an extracellular artificial antibody scaffold (scFv, single-chain variable fragment) that allows them to recognize specific antigens. These scFv-peptides are linked to CD8/CD3-ζ fusion receptors via a transmembrane-spanning amino-acid domain (mostly derived from CD28, a co-stimulatory protein in T-cells) that reaches into the cell. Upon binding of the respective antigen to the scFc-scaffold, these receptors would signal the T-cells to activate and cause an immune response. More recent designs added additional modules to potentiate and complement T-cell activating function of these receptors, improving overall therapeutic possibilities.
What sounds complicated might be easier to understand with an analogy to the military:
Scientists basically took out some soldiers to train them against their enemy, shared the how-to-defeat blueprint with the weapons factory, and send the equipped and trained soldiers back into the field to beat an enemy they know everything about.
CAR technology in the fight against cancer
However with cancer, there is always another problem. Cancer cells are technically not “foreign”, they are part of our body, sharing our DNA and protein makeup. While our immune system evolved to also keep an eye on our own misbehaving cells, tumor cells evolved many tricks to camouflage themselves from our immune system. For example, they might abuse normal cell communication pathways to signal the immune system to back off, or just make themselves invisible by not displaying certain proteins (antigens) on their surface. Unfortunatly, although many tumors express tumor-associated antigens, the uniqueness of these antigens is also of vital importance. We have around 200 different cell types in our body, so we have to understand that there is a good chance that if we target an antigen that is produced by the tumor, there will be other cells that are also being attacked as well just because they share the same antigen. If not careful, one would risk millions of “civilian” cell casualties just to kill a few rogue tumor cells, notwithstanding that if these million cells are necessary for survival, we would kill the patient as well. This is a HUGE safety concern for CAR technologies. Things are never easy with cancer.
Now to the good news;
It turns out that for certain cancer types, mostly blood-borne cancers, scientists have already found the right “antigen” to target, because it is almost exclusively used by cancer cells and some non-essential and replenishable B cells. Under generic names like “second-generation anti-CD19 CARs“, phase 1 clinical trials yielded excellent outcomes, including high rates of long-term complete remission in patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and acute lymphoblastic leukemia. To date, more than 300 patients are being treated with CAR therapies, and many more are to follow.
These unexpected positive outcomes encouraged a renewed hype with immuno-therapy; after scientists tackled problem after problem since two decades, we finally are at a point where we can proof that it works in certain disease circumstances. The economic response was immediate, which caused a surge of investment in the last 2 years for companies working on bringing CAR technology therapies to the market.
Now one has to be careful about hyped technologies, especially if featured as one of 10 breakthrough technologies of 2016 by MIT technology review, because people tend to be too optimistic with promise of new shiny technologies in the short run, while underestimating their potential in the long run. Especially in the medical field, which tends to be a slow adapter, it will very likely take more time for “Immune engineering” than just 1–2 years to really have impact.
However, the scientific idea to “upgrade” our immune system has already worked once, with vaccination, and its impact on human life and civilization was enormous. Modifying T-cells to target cancer is another big step toward immune system 2.0, with similar strategies to treat autoimmune diseases like type-1 diabetes or multiple sclerosis already on the radar.
If we can embrace the potential of our immune system, nothing is standing in the way of a glorious and healthier future. And maybe sooner than we think, it will be us standing at the hospital and hearing:
“Welcome, which disease can we cure for you today?”
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