CAR-T therapy against ALL  

October 28, 2017 0 By Michael
Reading Time: 4 minutes

CAR-T therapy against ALL

The game 

Kill the cancer with chimeric antigen receptor T-cell therapy. A cancer therapy based on genetic manipulation of T-cells to attack specific targets that would otherwise evade the immune system. 

The players  

T-cells  

The potential cancer killer. Cells of the adaptive immune system that are responsible for killing foreign invaders such as bacteria and viruses and with limited capacity to kill tumor cells.  

Chimeric antigen receptor  

The detection module. A genetically engineered protein that is designed to help the T-cell to recognize cancer-specific pattern and stimulate the T-cell to attack and eliminate the tumor. 

The cancer 

Obviously the enemy. Needs to be eliminated.  

A cancer-specific antigen 

The cancer’s achilles heel. A cancer-specific protein or part of a protein on the surface of cancer cell. Ideally it is unique to this particular cancer and not present on a normal cell.  

How does it play out? 

The immune system, so adept at fighting off bacteria, viruses and other pathogens, seems to struggle when faced with fighting cancer. There are a number of reasons for this. For once, your immune cells are trying to fight your own cells. Cancer cells have changed, yes, they behave differently but they are still your own. Still sort of look the same. Your immune system usually goes through great lengths not to kill your healthy cells, for obvious reasons, and for your T-cells, the ones that can potentially kill tumor cells, the distinction between tumor and healthy is not always black and white. Still, your immune system can home in on a tumor and start to fight it back. Cancer, alas, is a sneaky bastard. Once targeted the tumor will try to evade the onslaught of the immune system. It can hide from the immune system, it can convince a T-cell not to fire once recognized, it even creates its own microenvironment, a twisted ecology where the tumor can thrive and the immune system is forced to stand down.  

The chimeric antigen receptor (CAR) can help to nudge the T-cells into the right direction, stimulate it to fight the cancer. The CAR spans the cell’s membrane, the part of it responsible for recognizing the target faces the outside of the cell, the activation switch that readies the T-cell to kill the target faces the inside.  

Naturally occurring T-cells don’t have this CAR, or any CAR for that matter. It is an artificial design, a feat of genetic engineering. It’s a combination of two natural proteins: a fragment of an antibody designed against the target that needs to be recognized and the CD3 zeta chain of the T-cell receptor… Wait, the what? If you want to know exactly how it works have a look at our advanced immunology tutorials, for now it’s enough to know that it’s a protein that, when engaged, activates T-cells to kill their targets.  

Antibodies you have certainly heard of, the backbone of our long-term immunity. In CAR-T therapy researchers take advantage of the antibodies ability to very specifically recognize a pattern. Antibodies can be made to recognize pretty much everything on a molecular level. In our example of CAR-T therapy against ALL the antibody part of the CAR is made to recognize a protein on the surface of B-cells called CD19. It does not really matter what CD19 usually does, it’s only import that it’s on the surface of the B-cell so the T-cell can see it and that it is only on B-cells, so the T-cell won’t attack other cell types. If, for example, liver cells would have CD19 on their surface our engineered T-cells would go and kill your liver, with rather unpleasant consequences. Not being able to hold your liquor would be the least of your concerns. And that illustrates one of the biggest challenges these type of therapies face: the identification of unique patterns of cancer cells. The hunt for these cancer specific antigens is certainly on but so far with only limited success. Even CD19 is not a perfect target. It is only found on B-cells, which is good, but it is found on cancerous and healthy B-cells. That means CAR-T therapy targeting CD19 will eliminate the cancer but it will also eliminate all your B-cells. In this particular case it is not too dramatic since B-cell loss can be treated with medication and the benefits far outweigh the side effects. 

Another challenge is that the T-cells to be engineered need to be your own. We can’t just go ahead and produce a big batch of generic T-cells against CD19 and inject it into patients. That would cause graft versus host disease, a condition where the injected T-cells would attack the recipient’s’ healthy cells. T-cells from strangers lack a tolerance for our healthy cells, they will recognize them as foreign and try to eliminate them. That’s why for a successful CAR-T therapy your own cells need to be isolated, genetically manipulated, propagated and injected back into your system. A rather complicated and long process which we will explain in detail in the coming sections.  

But for now let’s summarize. CAR-T therapy is a targeted cancer therapy that relies on genetic engineering of your own T-cells in a way that they can specifically recognize and kill the cancer cells. Simple as that. Pass by again soon to learn about the following topics:

How do antibodies work?

How does a T-cell kill?

How does cancer evade the immune system?

The search for cancer specific antigens (cutting edge) 

Promises and limitations of CAR-T (cutting edge)           

 

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