CAR T Cells: Beating Cancer with the Immune System

It’s 1996. The doctor has bad news for Doug Olson.  He’s just been diagnosed with chronic lymphocytic leukemia, one of the most common types of blood  cancer in adults.

Fast-forward to 2010 - his cancer is still not under control despite years  of chemotherapy, and he’s running out of options. He decides to join a new clinical trial  testing an experimental cancer treatment: genetically modifying a patient’s own immune  cells so that they can kill cancer cells. Scientists called this “CAR T cell therapy”.

Miraculously, Doug’s cancer completely  disappeared. This success led to further clinical trials, research, and the approval of  the first CAR T cell therapy in 2017 as well as 5 more CAR T cell therapies targeting other blood  cancers. In 2020, Doug’s blood was studied again, and scientists found that his modified  immune cells were still patrolling his body, killing any cancer cells that appeared again.

His  doctors said his cancer was essentially cured. Remarkable, isn’t it? Right now, many of  the sickest cancer patients are getting invaluable extra years of life with CAR T  cell therapy.

This video will explain how this treatment works and what the future  holds for this revolutionary new therapy. CAR T cells are genetically modified versions of  T cells, which are immune cells with a variety of functions, one of which being the ability to  target and kill infected cells. To understand how CAR T cells work, we need to first understand  how T cells get activated during an infection.

T cell activation must be a tightly controlled  process because unnecessary activation of T cells without infection can lead to autoimmune disease  and damage to healthy tissues. To prevent this, T cells must get two signals to become fully  activated. This is going to get a bit technical with lots of different receptors, so bear with me  – it will help explain how the CAR T cell works.

The first signal involves the T cell receptor, a  fascinating structure that T cells use to detect pathogens. Specifically, they recognize chunks  of a pathogen, which are called “antigens”, like part of a protein from a virus. These  receptors slightly differ in structure between T cells, which allows different T cell  receptors to bind to different antigens.

These antigens aren’t just floating around  though – T cell receptors are picky because they only bind the antigen if they are held by  a special receptor called an MHC molecule. The MHC molecule is on another cell, like a dendritic  cell or another special antigen-presenting cell. The interaction between the T cell receptor  recognizing its specific antigen on the MHC molecule is the first signal, which activates  the T cell receptor signaling area called CD3ζ.

The second signal is called a costimulatory  signal and acts like a confirmation, double-checking that the body is indeed under  attack and the T cell should be activated. This second signal is usually activation of  the signaling area of a receptor called CD28, but scientists have discovered many other  co-stimulatory receptors, shown here. When both signals are received, only then  can the T cell activate and multiply.

One type of T cell, called a killer T cell,  will now look for infected cells to destroy. How does it know which cells are infected? It  uses its T cell receptor and looks for cells that have the pathogen antigen on their MHC  molecules, meaning there is pathogen inside the cell, and forces the infected cell to  self-destruct, a process called apoptosis.

After the infection is cleared, memory  T cells will lie dormant and become reactivated if the pathogen returns.  You are now immune to that pathogen. The incredible ability of T cells  to recognize a particular antigen, kill infected cells with that antigen, and create  long-term immunity, made scientists wonder if we could take advantage of this feature to create T  cells that can recognize cancer-specific antigens, kill cancer cells, and essentially, cure  cancer.

After decades of research, scientists made the idea of a modified cancer-killing  T cell a reality: this is the CAR T cell. CAR is an abbreviation for "Chimeric Antigen  Receptor". Much like the mythological Greek monster the Chimera, a combination of a lion, a  goat, and a snake, the chimeric antigen receptor is also a combination of different receptors  that allows the CAR T cell to recognize cancer proteins on the surface of cancer cells. 

This interaction activates the CAR T cell to destroy cancer cells in a similar method  of how killer T cells destroy infected cells. How does this work? This special receptor is  made of three sections, or “domains”.

The first part is the binding domain, which is designed  to bind and recognize the antigen of interest. The problem with a regular T cell receptor is that it only binds antigens if they  are displayed on an MHC molecule. It cannot directly recognize a surface protein  on a cancer cell.

To overcome this limitation, scientists decided to use special proteins  from B cells called antibodies – specifically, the arms of the antibody, which can be designed  to bind to almost any protein. By using one of those arms as the binding domain, the receptor  can now recognize cancer surface proteins. When this receptor binds to the cancer  protein, it needs to activate the T cell, so it needs a signaling domain. 

Remember - a T cell needs both the T cell receptor signal and a second  co-stimulatory signal to activate, so scientists have added the signaling domains  from CD3ζ and CD28 to the end of the receptor. There’s currently ongoing research on which  co-stimulatory molecule to use, with different combinations of co-stimulatory signals providing  varying effectiveness in different cancer types. Lastly, to connect the two domains inside and  outside the cell membrane, a transmembrane domain from another protein is used.

The segment  connecting the binding and transmembrane domains is called a hinge or spacer, which allows the  binding domain to be flexible when binding to the antigen, increasing its chances of successful  binding. And with these three domains, we’ve got ourselves a chimeric antigen receptor that binds  to cancer proteins and activates the CAR T cell. So how do we modify T cells to  have these special receptors?

Since this entire receptor is a protein, we can  take the different DNA sequences encoding the different parts, join them up, and deliver  into T cells, usually by a disarmed virus. First, a special machine filters out  white blood cells from patient blood, a process called leukapheresis. Then, in the  laboratory, the T cells are isolated from the white blood cells, and genetically modified. 

The modified T cells that express the receptor are selected and stimulated to proliferate into  millions of cells, then transfused back into the patient to start eliminating cancer cells.  This entire process takes around one month. As of 2023, there are six approved CAR  T cell therapies for blood cancers.

Four of them target the protein CD19 to  treat B cell leukemias and lymphomas, and the other two target BCMA  to treat multiple myeloma. CD19 and BCMA are proteins also found on healthy B  cells, so B cells are also destroyed during CAR T cell therapy and patients need careful monitoring  and replenishing of antibodies after treatment. CAR T cell therapies are currently used only after  other treatments have failed, and they still show remarkable success in these blood cancers.

For  example, in a recent Phase III randomized clinical trial of 386 patients with relapsed or treatment  resistant multiple myeloma, patients who received the CAR T cell therapy idecabtagene vicleucel had  higher rates of patients responding to treatment, higher rates of complete cancer elimination,  and a longer time being cancer free compared to current standard therapies. These impressive  findings are encouraging scientists to test CAR T cell therapy as an initial treatment rather  than a last resort, with promising results. We are also starting to realize that patients can  be cancer free for years after CAR T cell therapy, like in Doug Olson’s case.

Scientists think  that this happens when some CAR T cells turn into other T cell types or behave like memory  T cells. They then patrol the body for cancer cells for many years after transfusion.  This really is an incredible “living” drug!

However, this treatment isn’t without side  effects. Aside from depleting B cells, activated CAR T cells can also activate other  immune cells, resulting in the release of immune signaling molecules called cytokines.  The widespread activation of CAR T cells and other immune cells results in cytokine release  syndrome, which can range from a mild fever, which happens in most patients, all the way to  organ failure, which is rare but life threatening.

The severity of this side effect is dependent  on the amount of cancer originally in the body – more cancer cells will activate more CAR  T cells, resulting in more cytokines released and a greater severity of cytokine release syndrome.  Another rare side effect occurs when the cytokines also damage the blood-brain barrier and the brain  itself, resulting in severe neurological symptoms. This is called immune effector  cell-associated neurotoxicity syndrome.

These two severe side effects require careful  monitoring and treatment with immune suppressants, but most patients are able to recover from this. What does the future hold for CAR T  cell therapy? The most fascinating aspect of this therapy is really the  potential of genetic bioengineering.

Here are some cool ideas being tested  in the lab and in clinical trials. To make an even more specific CAR T cell receptor,  the receptor could be modified to recognize two different proteins, and both need to be activated  for killing. This is called a “Tandem” car.

Research is also ongoing to design CAR T cells  that work in solid tumors. Solid tumours are resistant to CAR T cell therapy because they can  express molecules that activate off-switches on T cells. “Armored” CAR T cells are genetically  modified to remove these off-switches, protecting CAR T cells from being disarmed, so they have  a better chance of destroying solid tumors.

Conversely, “self-destruct” CAR T  cells are genetically modified so they express an apoptosis protein that  is only activated in response to a drug. The idea is, if side effects are out  of control, a doctor can inject the self-destruct drug and the CAR T cells  will die, stopping the side effects. Lastly, CAR T cells have to be made from a  patient’s own T cells to prevent transplant rejection.

Right now, scientists are working on  creating a “universal” CAR T cell that can be transfused into anyone and essentially used  right off the shelf like other medications, which could dramatically reduce manufacturing time  and the cost of this highly expensive therapy. These are just a sample of “power-ups” for  CAR T cells, with many more being developed and researched, as well as other creative  ideas such as using other types of immune cells or using CAR T cells to prevent autoimmune  disease – more on this in the description below. While there are still challenges to overcome,  including better management of side effects, lowering costs, and targeting more  types of cancer like solid tumors, CAR T cell therapy represents a  breakthrough in cancer therapy, offering hope to patients who previously had no  treatment options left.

Continued research will improve this relatively new therapy into an even  more effective tool in the fight against cancer. Thank you all for watching and supporting  this channel. If you have requests for future video topics, I’d love to hear  them!

Leave them in the comments below. And as always, see you next time on Medicurio.