CAR-T Cell Therapy Enhances the Immune System and is the Closest We Are to a Cancer Vaccine
An explanation of CAR-T Cell immunotherapy and the mechanisms by which it treats cancer
In 2015, Scott McIntyre was given four months to live.
The diagnosis was obvious: a malignant B-cell lymphoma that had spread to the lungs. His doctors had tried everything — several rounds of chemotherapy, a stem cell transplant, and targeted radiation therapy, but the cancer kept coming back.
His doctors were almost out of options. They proposed an experimental and uncertain immunotherapy called CAR-T cell therapy. His own immune cells would be taken from his body, genetically engineered, and infused back into his blood in an attempt to destroy the cancer. There were no guarantees that this would work, but at the very least, scientists would be able to learn more about his cancer and how he responded to the therapy.
McIntyre had nothing left to lose and so went ahead with the procedure.
Five years later, and he is still cancer free.
This story is one of many happy successes of CAR-T cell therapy against blood cancers, championed as “Cancer’s Newest Miracle Cure” by Time Magazine. This innovative, interdisciplinary therapy is at the cutting edge of science, combining elements of genetic engineering, immunology, and cancer therapy to re-design immune cells and re-train the immune system to attack cancerous cells, much like it already does for bacteria and viruses.
This “living and dividing drug” can persist in the body for years, continually patrolling the body in order to ensure the cancer doesn’t come back.
More specifically, CAR-T cells involve re-engineering the targeting mechanism of specific immune cells called T cells. All cells have distinct protein markers on their surface called antigens. For example, the spikes on SARS-CoV-2 are a distinct structure that allows the body to recognise the virus. These T cells patrol the body, examining antigens to identify whether a cell is foreign or normal, healthy or cancerous.
Once a foreign or cancerous cell is discovered, the T cell binds to the antigen and enters an activated state. A chain reaction occurs, resulting in the T cell rapidly duplicating itself into a small army. These T cells then induce cell death by puncturing the cell walls, causing the inner contents to leak outside of the cells.
However, some tumours undergo escape mechanisms and become invisible to the natural immune system. T cells are no longer able to recognise the antigen, meaning the cancer is able to grow unchallenged. Thus, scientists must find new ways to target the tumour.
It was recently discovered that it is possible to redesign the existing T cell receptor via genetic engineering to create an artificial receptor that can bind to specific proteins. These artificial receptors are known as Chimeric Antigen Receptors (CAR), combining multiple functions into one receptor such that T cells can more effectively target and destroy cancerous cells.
In clinical trials where the cancer kept relapsing and all other treatment options had been exhausted, CAR-T cell therapy resulted in a 90% remission rate in acute lymphoblastic leukemia and 86% sustained remission for diffuse large B-cell lymphoma.
The procedure for this revolutionary immunotherapy can be broken down into four main steps:
- Identify the target and extract T cells from the blood
- Genetically engineer the T cells to express the CAR
- Duplicate the CAR-T cells and infuse them into the body
- Monitor the patient as the CAR-T cell's target and kill the cancer
1. Identify the target and extract T cells from the blood
Every cell in the body has receptors on its surface that are used for the communication and transportation of nutrients. These receptors act as identifying markers that can be selectively targeted. However, most cells share receptors, so scientists seek to target receptors that are highly expressed in cancer cells but less expressed on the rest of the cells within the body. Finding the perfect receptor can be difficult, often requiring compromises.
In the case of CAR-T cell therapy for leukemias and lymphomas such as the one McIntyre suffered from, a popular target receptor is CD19. However, while this receptor is highly expressed on the cancerous cells, CD19 is also expressed on B-cells, the antibody-producing factories of the immune system. CAR-T cell therapy thus can result in the death of healthy B-cells alongside cancer cells. Fortunately, this loss is tolerable and can be combated by regular antibody injections throughout the duration of the treatment.
Once the target has been identified, the T cells are isolated from the blood through a process called leukocyte apheresis. A tube is inserted into each arm, whereby blood is taken out through one tube and passed through a machine that filters the blood and isolates the T cells. The filtered blood is returned to the body through the second tube.
2. Genetically engineer the T cells to express the CAR
Scientists exploit the fact that viruses already have the biological machinery to modify the genetic material of another cell. The now isolated T cells are genetically engineered using a virus as a vector for the genetic payload.
The CAR gene is inserted into the virus. The virus then travels to the T cell and enters it, just like how a normal virus usually infects a healthy cell. The virus releases the payload into the T cell and CAR gene is inserted into the DNA. This means that the T cell now has the genetic information to produce the CAR on its surface.
3. Duplicate the CAR-T cells and infuse them into the body
Growth factors and cytokines (chemicals that stimulate an immune response) are added to encourage the T cells to differentiate and proliferate. This results in the generation of many T cells, each expressing CARs on their surface. These CAR-T cells are then infused into the body via injection.
4. Monitor the patient as the CAR-T cells target and kill the cancer
The CAR-T cells, having had their targeting systems augmented via genetic engineering, are now capable of detecting the cancerous cells. They patrol the body, and once they find their target, they latch onto the cell surface receptors and ready themselves to destroy the cell.
An immune synapse is formed, acting as a pathway for cytotoxic granules containing perforin. This enzyme is capable of puncturing the target cell’s membrane, causing its contents to spill out as it dies. These CAR-T cells go on killing sprees — the more cancer cells they find, the more inflammatory signals they release, and the more aggressive they become.
Additionally, these CAR-T cells are a particularly powerful treatment, as they are able to ensure durable cancer remission. Cancer cells can enter into a protective “hibernation mode” during chemotherapy, rendering them difficult to fully eliminate. However, in CAR-T cell therapy, the genetically engineered T cells act as a “living drug”, continuing to patrol the body and using their augmented targeting system to ensure that no cancer cells survive.
While CAR-T cell therapy does seem like a miracle cure, it does have some existing limitations. Some patients suffer from Cytokine Release Syndrome (CRS), whereby their immune system becomes overactive and triggers system-wide inflammation, which can cause organ failure. Additionally, while this therapy is capable of treating blood cancers, scientists are struggling to adapt it to common solid tumours.
However, CRS has been well studied and is currently treatable using a drug named “tocilizumab”. Additionally, progress is being made in the treatment of solid tumours, which are slowly able to be more effectively treated.
Currently, two therapies are FDA approved: Kymria and Yescarta, with many more currently undergoing clinical trials. These existing and upcoming therapies are incredibly promising and are positioned to completely revolutionise the field of immunotherapy and cancer treatment.
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