A one-size-fits-all cure for cancer?

Mechanisms of cancer, CAR T-cell therapy and a new promising treatment

Apr 19, 2020

Abstract

Something very clear now is that cancer is a genetic disease. This means it happens at the cellular and molecular levels, and there are specific genes that if mutated, can be highly influential in its development. Despite that, the problem with fighting cancer has continued to be that most treatments are not efficient, nor accurate enough. This Emperor of All Maladies has been attacked from the outside, when its root cause is in found our deepest inside: in our DNA.

This war is also being fought by our immune system. Nevertheless, this hasn’t been enough. Therefore, scientists have come up with a revolutionary idea: enhancing our immune cells so they get better at identifying cancerous cells.

New therapies of this kind are being developed constantly. This year, an immunotherapy which could overcome many limitations has arrived. The therapy was able to kill more than 80% of cancerous cells, without even reacting to healthy cells, in addition to being suitable for a wide range of people. MR1 is the main molecule here and it is HLA-independent. Is this the one-size-fits-all treatment we’ve been waiting for?

The Cell Cycle

We have heard the word cancer lots of times. But we also need to understand it from a more biological perspective. The two most important things you need to know about this disease are: cancer is not a single disease since there are more than 100 types of cancers. Instead, it is a type of disease that can happen to pretty much any cell. The reason for this (the second thing you need to know) is that cancer is a disease that consists of uncontrollable cell growth.

What we mean by growth here can also be referred to as division, multiplication or replication. For this we need to understand that when a cell wants to replicate (make another cell or have a daughter) it needs to split into two.

Now, in order for a cell to grow and divide (and to keep you alive) it needs to go through a cell cycle which is pretty much like a life cycle. First of all, it needs to grow (G1 phase), then it has to multiply its DNA (S phase), after that it can continue growing (G2) and finally it can split into two cells (M phase/Mitosis).

Since we want everything to be kept in order in the cells and we don’t want any DNA damage or uncontrollable cell growth, cells are really smart and have established checkpoints between each phase. So, if a cell wants to go from G1 to S, two proteins will need to be produced. Those are CDKs and Cyclins.

A cyclin, as its name suggests, is the main cell cycle regulator protein. Furthermore, there are specific types of cyclins for each phase of the cycle, and each of them increases their expresssion in their corresponding phase. But cyclins don’t work alone. In order for the cell cycle to continue, cyclins need to activate the Cyclin-Dependent Kinases (CDKs). Together, they are the “drivers” of the cell cycle.

Genes of cancer

Moreover, CDKs and cyclins are not independent drivers of the cell cycle. In fact, they are created by a specific type of genes called proto-oncogenes. These are a type of genes that are normally present in all of our cells and are in charge of functions like regulating gene expression, cell growth, cell death, DNA repair or inhibiting CDKs and cyclins.

For example, Ras is a proto-oncogene a protein that sits on the surface of cells and interacts with a growth factor receptor (GFR). As its name suggests, the GFR receives signals from outside of the cell and “tells” Ras protein when it is time to divide. Then, Ras activates a transcription factor that makes the production of CDKs and cyclins possible. In other words, we could say that Ras indirectly controls the expression of CDKs and cyclins and as a consequence, the cell cycle. At the same time, it is worth to mention that the moment in which proto-oncogenes become the villains of the story is when they are mutated.

A question worth answering is what are mutations and why are they caused? Mutations are errors that happen when your genes are being “read” to create a protein or to multiply. There are different kinds of mutations: point mutations (change in a single nucleotide), amplification of genes (a gene sequence is copied more times than it should), chromosomal translocation (genes are exchanged between chromosomes) or DNA methylation (“tags” are added to your DNA that don’t allow the cell to read it correctly).

Double strand break in the DNA can be caused by X-Rays or Gamma Rays. Image credits: TED-Ed

These can happen due to some many of different factors such as physical or chemical carcinogens (like radiation), eating habits, environmental conditions or viral infection. Although we should keep in mind that there also exist beneficial mutations like natural selection, most of the time we would like our DNA to stay the same.

Turning back to Ras, we can now infer that if it is mutated, it would be active all the time and as a consequence, more CDKs and cyclins would be produced, the cell would pass from one phase to the other, ultimately leading to uncontrollable cell growth: cancer.

Overall, what you need to remember is that any proto-oncogene can turn into an oncogene if it is mutated and oncogenes are closely related to uncontrollable cell growth. As a result, we could even affirm that cancer is a genetic disease that has as a root cause the transformation of proto-oncogenes into oncogenes.

Current treatments

The fact that cancer is such a complex disease fortunately hasn’t stopped scientists from fighting it. So, let’s talk about some of the ways scientists and doctors can treat cancer.

Chemotherapy is one of them and it involves the use of certain chemicals to make damages to cells’ DNA. It is administered through the bloodstream so it can easily reach parts of the body that have cancerous cells. The reason why it is used is that when cells need to divide they expose their DNA, and since cancerous cells are the ones which divide more rapidly, they are killed the most. Even so, this therapy has a huge disadvantage, and it is that it doesn’t prevent healthy cells from being killed, leading to horrible side effects and overall damage to the rest of the body.

As for other treatments, most cancer patients go through a process of surgery to extract the tumor from the body and then chemotherapy or radiation therapy to get rid of the cancerous cells left behind.

As you may imagine, the problem with all these treatments, including chemotherapy, is that they are sometimes tested in the lab in one way but they can work in a whole different way when tested in patients. This can be mostly because when cancerous cells replicate they can produce mutations in their DNA that lead to subclones. In other words, there are subtle changes in one single cancer. Not to mention the horrible side-effects that patients need to suffer from and overall, the lack of accuracy as a lot of healthy cells are also killed in these kinds of treatments.

A secret weapon

Despite everything , the truth is that our own body is actually capable of fighting this emperor of all maladies. Indeed, the secret lies in the more than four thousand white blood cells that are doing their best to keep you healthy every day.

The immune system is one of the 11 body systems that you have. It is basically in charge of protecting you from disease and keeping you healthy. This is, it fights invaders in your body.

White blood cells (also called immune cells), belong to this system and there are five major types of them. The ones we will be focusing on in this article are called T cells.

These immune cells are specific to each individual. Meaning, my T cells are not going to behave the same way as your T cells. In addition to that, there are also many types of T cells, including cytotoxic, helper, regulatory, natural killer, and memory T cells. Although they can also distinguish infected or cancerous cells, recognize antigens or call other white blood cells, their most important “mission” is to recognize invaders. The way they do this is by using their most important tool: the TCR.

A TCR (T Cell Receptor) is like an antenna that allows T cells to do their job. As its name suggests, it receives signals from the outside of a T cell, which is always searching for proteins on the surface of other cells. If it doesn’t recognize the proteins or thinks they’re not part of the organism, it tells the rest of the T cell to call other immune cells or to switch the cell death on (in case it is a cancer cell).

The reason why this system works is because almost all of your cells need to have something like a passport in the molecular world: the HLA. This is a complex of proteins in the surface of human cells that show T cells what they’ve been up to (they show them the proteins that are being produced inside them).

If you think of this this is in an analogy, it would be like going through migration and showing the officer your passport so they can see where you’ve been. If there’s something suspicious, they’ll probably need to call other officers (white blood cells).

Important to say, the HLA complex consists of more than 200 genes, which are categorized as Class I, II or III. At the same time, class I genes are subdivided into HLA-A, HLA-B and HLA-C which are expressed on the surface of the cells. There are six main MHC class II genes in humans: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. These are expressed exclusively in immune cells and also show other immune cells what’s inside them. The proteins found in the III group are in charge of other functions such as inflammation but some of them remain unknown.

Something to keep in mind is that HLA is the MHC (Major Histocompatibility Complex) that we humans have. And an antigen is normally a structure in the surface of pathogens that makes our immune system react. However, in this case, the HLA is a type of antigen that’s present in most of our cells and displays samples of proteins that are being made inside the cell to T cells so they can decide whether the cell is cancerous, has been ‘hacked’ by a virus or if it is completely healthy and it isn’t a threat for the rest of the organism.

A new approach

We now know that our own body can fight cancer. However, is it really that efficient and strong enough to do it by itself? Well, though it depends on each person’s organism, in most cases the answer will be no.

One of the main challenges that our immune system faces is that cancerous cells can hack the cells’ innate system so it doesn’t express antigens correctly, making it more difficult for T-cells to identify them.

Nevertheless, this doesn’t mean we cannot use the immune system to be victorious in this war. By saying “use” the immune system, we mean that we can take these wonderful cells that all of us have and give them the tools they need to be more efficient and accurate to kill cancerous cells.

The way scientists are doing this today is by genetically modifying white blood cells so they express certain TCRs and become better at recognizing cancerous cells.

One of the most popular therapies right now is called CAR T-cell Therapy (CAR stands for Chimeric Antigen Receptor), which consists of three steps:

Taking blood from the patient: as it would be done for any other study
Separate blood components: blood is put into a centrifuge machine to separate white blood cells from red blood cells, plasma, and platelets
Culturing white blood cells: using a pipette we take out the plasma layer, which should be now on top of white blood cells. Then, white blood cells are cultured (grown) in a separate flask.
T-cells are genetically modified using tools like CRISPR
Modified cells are grown in culture: basically, so we can have as many of them as possible (it’s like having as many soldiers as possible for a battle)
Modified cells are infused into the patient again: so they fight cancer now being smarter and stronger

A little big problem

CAR T-cell therapy is one of the most revolutionary treatments out there and the closest we have been to defeating cancer. Efficiency is incremented together with reducing side-effects and it’s becoming more accessible to more patients each day.

Still, one major challenge that hasn’t been overcome yet is the fact that it needs to be tailored to each person’s HLA type (which we have talked about earlier in the article).

Personalized medicine is a lot of times considered as the future of medicine. In the past and up to date, one single type of medicine has been used to treat millions of different patients, which is now considered as a mistake. We are all different from the very deep in our DNA, thus giving patient A a medicine that only works for patient B is not going to work well in most cases.

Now, what we shouldn’t confuse is a medicine that can suit patients A, B and C from a medicine that only works for A and is given to B. What scientists have found earlier this year is probably a treatment that can suit most patients.

The one-size-fits all

On January 20th, researchers from Cardiff University published a paper in Nature called Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer target via the monomorphic MHC class I-related protein MR1. I know this title is too long, but we can easily break up the confusing words in it:

Ubiquitous: that can be found everywhere.
Monomorphic: something that has or exists in only one form.
CRISPR-Cas9: gene editing tool (we’ll talk about how it’s used in this experiment later).
MHC class I-related: MR1 is present in a wide variety of cells, just as if it was an MHC class I protein.

The great discovery was finding a molecule that doesn’t work via the HLA pathway. Remember that one of the disadvantages of CAR T cell therapy was that it had to be tailored to each person’s HLA? Well, scientists have found a molecule that does pretty much the same thing, only it doesn’t vary a lot throughout the human population. This sounds quite good, but is it present in different types of cancer? is it accurate? is it effective?. To answer these questions and know the wonderful outcome of the experiment, we first need to know what MR1 is and where it comes from.

MR1 is a gene and it codes for a protein that is also called MR1. In a natural situation (without any biohacking) this protein is stored in the endoplasmic reticulum. When it’s time to do its “job” it is sent to the surface of cells and is presented to a type of T cells called MAIT (Mucosal Associated Invariant T). MR1 displays samples of the proteins that are in the cell. Another reason why this protein is amazing is that it can present a broad range of ligands (proteins).

It’s also important to know its origins. MAIT cells are immune cells found in the blood, liver, lungs and mucosa which have the role of defending against microbial activity and infection. As mentioned before, they collaborate with MR1 molecules so they can induce inflammation and fight infected cells. They also have a TCR, called TRAV1–2 with which MR1 interacts.

The great outcome

Now it’s time to dive into the real interesting thing. Because even when all of the previously explained is already quite interesting, the results of the experiment were absolutely astonishing, in my opinion.

Interestingly, the purpose of the experiments wasn’t finding a cure for cancer. Nevertheless, after they discovered MR1, they engineered T cells to express it, which were able to kill cancerous lung, melanoma, leukemia, colon, breast, prostate, bone and ovarian cells that didn’t share a common HLA. Not only that, but they also had more than 80% of efficiency when killing cancerous cells and in some cases, even all 100%. In terms of accuracy, what truly does this T cell therapy outstanding is that it did not respond to any of the healthy cells.

Regarding CRISPR, researchers used it to know which genes T cells were using to identify their target. 6 gRNAs that can target every coding DNA in the genome and they found six important genes: b2M, MR1, RFXANK, RFX and STAT6. From these, RFX, RFXANK and REXAP are MHC promoters and b2M works with MR1 to form a molecule that activates MAITs and other T-cells that work with MR1.

To sum up, researchers involved in this experiment think that the reason why MR1-egineered cells can be so reliable, accurate and efficient is because MR1 could be essential for the survival of cancer cells. Though the way in which T cells communicate with MR1 remains doubtful. A possible answer is that they use riboflavins (vitamin 2).

Could there anything more impressive than this? There is! Very low levels of MR1 were required so that T-cells could recognize them and cells engineered with MR1 TCR redirected the patient’s “normal” T-cells to kill cancer cells without a specific HLA. In other words, edited cells “trained” the others to kill cancer.