CAR T-Cells: The Key that's Unlocking Cancer
Cancer. Despite how much the world has changed, the way an average person views cancer hasn’t. The field of immunotherapy has been growing rapidly, with CAR T-Cells posing an opportunity to finally change our view on cancer. So cancers…
Cancer Deaths Haven’t Decreased
Cancer is the cause of 1 in 6 deaths. Over a span of 27 years, cancer deaths have only decreased by 2%! The crazy thing is…the National Cancer Institute predicts cancer cases will increase by 2030 to 23.6 million.
Radiation, chemotherapy and surgery are not enough. They are clearly not effective while causing many side-effects. And they have been around for 80 years! The same treatment does not work for every cancer case.
Imagine your trying to get buff. Blasting yourself with drugs and using other external sources is not sustainable. You have to build the real muscle from the inside, but you can use supplements and good nutrition to make that a possibility.
Immune System, Do You Even Lift Bro?
- Defence 1: Macrophages and Neutrophils — most of the time, these phagocytes and your skin is enough to block invaders
- Defence 2: Natural Killer Cell — they kill
- Defence 3 (calling in the big boys): T-Cells and B-Cells — these lymphocytes are what lookout for cancer
All of these defences are constantly working in your body to stop the constant incoming bacteria and viruses.
Putting it to the test: A Cancer Simulation
T-Cell Receptors (TCR) have a shape that binds to a molecule (MHC or HLA). These molecules contain peptides (broken down proteins) that exist in every cell. Some of the molecules will flow to the surface of the cell, where they are scanned by T-cells.
Think of MHC as the bottom of a scanner and the peptide as the paper. The receptor is the scanner piece that can move up and down. Once the scanner piece is closed, on top of the paper, it can read it’s contents.
Most scans tell T-cells, everything is fine and the cell is healthy.
But, in cancerous cells, mutations in the DNA can cause the production of different proteins and therefore different peptides. For example, smoking can cause a change in the peptide, often found in the lungs. These protein changes can affect processes like proliferation, causing cells to grow uncontrollably.
The T-cell recognizes the peptide change and signals, often CD 3 (a protein inside the T-cell membrane), which releases factors and weapons to kill the cancerous cell.
T-cells target unhealthy cells in general, not just cancerous cells.
B-Cells will produce antibodies, excellent at recognizing unhealthy cells. An antibody will attach to an antigen outside of a cancerous cell. This stunts the cell, allowing the other defences to kill it.
Antibodies must be the right shape to attach to an antigen. Over time, memory cells can remember the shapes of antigens and release the necessary antibodies when the invader appears again.
Think of a key as the antibody, and the lock as the antigen. If the key doesn’t fit the lock, the cell is healthy.
Despite the response: cancer can reach the escape stage — more cancerous cells are made than are destroyed.
Why: The Immune System ain’t Lifting Yet
- A T-cell may recognize the cancerous cell, but the release of killing factors doesn’t match the speed of proliferation (cells are growing faster than dying).
- The T-cell can’t read a peptide because it’s shape does not match or the MHC molecule is not holding the antigen.
- Cancerous cells can form a membrane, blocking T-cells from scanning the peptides.
- Cancerous cells can release factors of their own, deactivating a T-cell.
The deactivated T-Cell can transfer factors, like cytokines, deactivating other T-cells.
All of these problems affect our body’s ability to take down cancer. None the less, our immune system prevents the most amount of cancer deaths.
Immunotherapy: A New Treatment Option
Immunotherapy looks at using the immune system to fight off and decrease cancer growth. It can help buff up the immune response in two ways:
- Make the immune system stronger
- Affect a tumour’s environment and ability to suppress unwanted responses
CAR T-Cell Therapy
This specific type of immunotherapy tries to make T-cells buff (aka. treatment option 1). The T-cells have been genetically engineered to carry a new receptor, helping them recognize and kill cancerous cells at the speed of light!
How it Works
CAR T-cells combine a B-cells ability to quickly and correctly recognize unhealthy cells (scFv), and the T-cells ability to kill (signalling domain).
Given the type of cancer you have, a specific receptor is designed to match its antigen.
- Single-chain variable fragment(scFv) — the new receptor (CAR) which aligns with the antibody on the targeted cancer cell.
- Spacer — Connects the transmembrane domain and CAR.
- Transmembrane Domain — connects the scFv which if outside the cell membrane to the rest of the cell and holds the CAR in place.
- Costimulatory Domain — regulates the cytokine and factor production. This helps the cell react only when needed, preventing auto-immune diseases. Commonly CD28
- Signaling Domain — Allows the release of factors and cytokines, which kill the cancerous cell. Commonly CD3
The CAR ensures the cancer cell can be recognized, given its different shape and if the MHC protein is not present. The rapid attack ensures cells are dying faster than the rate of proliferation.
Bonus: These CAR T-cells stay around, continuing to fight unhealthy cells.
Behind the Curtain: Genetically Engineering T-Cells
Viral Vectors and CRISPR Cas-9 allow us to edit the genetic code of common T-cells, changing the receptor to the desired version, along with implementing other features. Here’s the viral vector approach:
- Take the genetic code for the desired CAR
- That is then inserted into a packing line containing the HIV retrovirus (the virus can’t replicate). The retrovirus just packages the CAR so that it can be inserted into the patients T-cell
- Activate the patients T-Cells which are extracted through apheresis (think of donating blood, but instead of extracting blood, we are extracting T-cells)
- Insert the retroviral particles (also known as viral vectors) into the T-cells
- You got CAR T-cells!
You can then perform ex-vivo cell expansion, ensuring there are enough T-cells to fight the cancer. Finally, the patient gets their buff CAR T-cells. Results…
That’s right, Yescarta and Kymirah are FDA approved and are being used to treat lymphoma. While many other CAR T-cells are already in clinical trials.
After receiving treatments, 75–85% of cases showed no cancer cells!
The Future
This is just the beginning for CAR T-cells. Of course, they have drawbacks and are nowhere close to reaching their full potential.
Drawbacks: Body’s Response
Some patients will experience cytokine release syndrome after the treatment. As T-cells release cytokine, it activates macrophages to release cytokine as well, creating a loop.
This causes an overactivation of the immune system and many symptoms. If caught and treated early, 95% of patients will survive.
Target Restrictions
Currently, CAR T-cells only work on lymphoma and leukaemia cancers (manly blood cancer). The common scFv used is CD19, a receptor present on most blood cancer cells.
But that's what we are limited to. Solid tumours can’t be treated because we don’t have a good receptor that matches the tumour’s antigen and the environment is much harder to access for T-Cells.
Cracking the code to CAR T-cells is all about finding a receptor that can kill cancer cells, while not affecting healthy cells.
New receptors are constantly being investigated and tested, hoping we can target down any cancer.
Key Takeaways:
- We have been using the same cancer treatments for over half a century with little change in the # of cancer deaths
- Immunotherapy takes advantage of our immune system, which already saves many people from getting cancer
- CAR T-cells are a buffed up version of T-cells, they can quickly recognize and kill cancer cells
- Developing new CAR T-cell receptors is key to killing every type of cancer
CAR T-cells will drastically change how we treat cancers. One day, CAR T-cells may be inserted in everyone as a baby, just to ensure almost no growth of cancer ever occurs. To make that a reality, innovation in receptors and other immunology treatments need to be developed.
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