Simon Pagaard Nielsen

Molecular Biology student and science communication enthusiast

January 22, 2018

CAR T-cell therapy: Teaching an old immune system new tricks to fight cancer

For many years, the main types of cancer treatment have been surgery, radiation, and chemotherapy. But now, with the emergence of new types of cancer therapies, that may be about to change.

CAR T-cell therapy, a type of immunotherapy that can be used to treat cancer by strengthening the patient’s immune system so that it can attack tumors, was recently approved by the FDA.  

The potential of this type of treatment is immense, and although it’s an incredibly sophisticated procedure that involves the manipulation of the patient’s own cells, it’s also a fascinating treatment that deserves a spotlight and a deeper look into the nature of its abilities.

To better understand this treatment, we'll need to take a closer look at the core part of it: the immune system.

When the immune system encounters cancerous cells

One way to describe what may happen to the immune system when it first encounters cancerous cells is to compare it to a student taking an exam:

As students, our main goal is to learn new things. Our knowledge is tested in an exam, where we have (of course) studied so hard that we know the curriculum by heart, and we are able to answer all the questions. The goal is then to pass the subject and go on to learning about the next new thing.

Now imagine yourself sitting at one of these exams.

You have (yet again) studied so hard that you know the entire curriculum by heart, and you are able to answer each assignment with ease.  

But then you encounter a problem you never experienced before: You turn the page, and it turns out to be blank.

Blank page

You ask your professor if some kind of mistake has been made. But it is not a mistake. There is, indeed, an assignment on the blank page.

But you can’t see any assignment. To you, it’s a just blank page.

What now?

Nothing.

You can’t solve the assignment, so you leave the page blank.

Like students, immune systems are faced with certain assignments. For example, immune systems have the ability to recognize different structures, both familiar ones (our own tissues) and foreign ones (viruses, bacteria or infected cells).

When foreign structures are identified, the immune system knows the appropriate response: to destroy them and ensure the health and safety of our bodies.

However, if the foreign structure is not identified or recognized, the immune system cannot respond.

In other words, the immune system will react to it like you reacted to the blank page at the exam.

So, what does it do?

Nothing.

The page is left blank and the foreign object cannot be destroyed.

Cancer: the blank page

Cancer is a conundrum to the immune system: It is inherently familiar as it develops from our own cells, but it is also dramatically different from all other cells in the body.

There are many types of cancer, all distinct in cause and location. Despite that, they all have several attributes in common. These are called the hallmarks of cancer. One of the hallmarks is the ability to avoid immune recognition through various mechanisms, thus allowing the cancer to multiply and avoid destruction.

That means the cancer seems like a blank page, making it difficult for the immune system to recognize it.

When the cancer is not recognized, the immune system simply cannot destroy the cancerous tissue.

CAR T-cell therapy: filling in the blanks

Scientists have long sought to exploit the immune system or mimic immune functions to treat cancer. A lingering question has been: Can we teach the patient’s own immune system to recognize cancer and destroy it?

Finally, this year, the question was answered with a resounding “yes” when the FDA approved YESCARTA™, the second chimeric antigen receptor (CAR) T-cell therapy for patients with certain types of progressing large-B-cell lymphomas (that do not respond to regular therapy). It seemed that the scientists reached a tipping point, allowing the progress in this field to accelerate.

Now,  let’s dig a little deeper into how the treatment works.

How does CAR T-cell therapy work?

CAR T-cell therapy teaches the patient’s immune cells to recognize the cancer, activate the immune system, and kill the cancer.

The therapy takes advantage of a type of adoptive cell transfer, which means that it involves the transfer of cells into a patient with the purpose of fighting a disease. The cells in question are, as the name implies, T-cells, a type of white blood cell.

CAR T-cell therapy process

One of the functions of T-cells is to recognize certain parts of foreign or cancer-related molecules, called antigens, on the surface of our own cells. T-cells accomplish this with receptors that bind a specific antigen. A way to think of receptor and antigen-binding can be to imagine a key (the antigen) fitting in a lock (the receptor). The binding primes the cell for destruction by the immune system.

Let’s break down the steps of CAR T-cell therapy a little:

Step 1

The first step of CAR T-cell therapy is to obtain T-cells from the patient’s blood. This is done by filtering the patient’s blood through a machine that separates the T-cells from other types of blood cells.

Step 2

Then, the T-cells are modified in the laboratory to produce a receptor that can recognize an antigen on the surface of a cancer cell. This involves several smaller steps:

Chimeric antigen receptor (this is the CAR part of CAR T-cell therapy) means that the receptor is made of different parts of several receptors. In other words, the best parts of multiple receptors are combined to create one receptor with efficient antigen-binding and immune activation.

To make the T-cells produce this engineered receptor, some help from another, perhaps unexpected, part of nature is utilized: A virus.

Try out our Viral Gene Therapy simulation to learn more about how modified viruses can be used to treat human diseases.

The T-cells are infected by a disarmed retrovirus, which causes an insertion of viral DNA into the genome of the T-cells. The inserted viral DNA carries a DNA sequence for the chimeric antigen receptor. Under the right circumstances, the insertion into the T-cell genome will lead to production of the CAR and its subsequent placement on the surface of the T-cell membrane.

The T-cells have now ‘learned’ to identify the cancer antigen, and the T-cells can recognize the previously blank page (the cancer) and activate the immune system to destroy the cancer.

The cells have hereby become CAR T-cells.

Step 3

Next, the CAR T-cells are allowed to multiply in the laboratory.

Step 4

Finally, the CAR T-cells are re-injected into the patient. Here, the modified immune cells are free to roam all over the patient’s body and to hunt for cells presenting the antigen on their surface.

Take a look at this 3D animation of the entire process to get an even better idea of how CAR T-cell therapy works:

A miracle cure?

The recently FDA-approved CAR T-cell therapy YESCARTA™ is engineered to recognize the CD19 protein on the surface of B-cells, another immune cell and the culprits of B-cell lymphomas. The results of the clinical trials that led to the FDA approval of YESCARTA™ for B-lymphoma treatment are impressive and the effect seems to be lasting. The fact that the patients in the clinical trials had either relapsed cancers or were not responding to traditional treatment makes the results even more extraordinary.

However, CAR T-cell therapy is not a miracle cancer cure. At least not for now.

The treatment is currently only administered as a last resort, when chemotherapy and all other treatment has failed.

On top of that, CAR T-cell therapy can, like all other forms of cancer treatment, induce serious side effects, for example, cytokine-release syndrome and a reduction of the amount of normal B-cells, as the CD19 antigen is also present on normal B-cells.

The treatment is also extremely expensive, listed at 373,000 USD. The production cost of the treatment needs to be lowered to make it more accessible, and one suggestion in this regard is to use donors for harvesting T-cells.

Finally, as for most cancer treatments today, sadly not all patients respond to the CAR T-cell therapy as planned.

But herein lies the true potential of CAR T-cell therapy: In theory, you can target another cancer antigen if the patient does not respond to the first CAR T-treatment. YESCARTA™ is engineered to target CD19, but one could imagine that if we acquire knowledge of the presence of other cancer antigens, a new treatment could be developed against the second antigen.

So, if the first bullet misses, and the patient does not respond to the first treatment, you have a second shot in the form of another CAR T-cell therapy targeting another antigen. All you need, in theory, is knowledge of the cancer and resources to develop the treatment. Such work is actually already being done, as scientists are exploring the CD22-antigen as a potential target for CAR T-cell therapy for B-cell lymphomas that do not respond to CD19 CAR T-cell therapy.

What next?

There’s still much knowledge to be gained and put to practice in this field, and there’s much ground to cover before CAR T-cell therapy can in fact be considered a ‘miracle cure’:

The therapy needs to be cheaper, side effects must be managed, and new CAR T-cell therapies for other types of cancer, for example breast and colon, must be developed and evaluated before the true impact of CAR T-cell therapy can be assessed and compared to the theoretical potential.

Despite all that, the fact that these treatments are slowly reaching the market is a promise of much bigger things to come. After all, it wasn’t long ago that we considered such extensive molecular modification to be something out of a science fiction book.

Even though CAR T-cell therapy will not eradicate cancer as a human disease and cause of death, we now have yet another sophisticated weapon in our arsenal for the fight against cancer.

 

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