What is CAR T-Cell Therapy?
CAR T-cell therapy is the most common and heavily studied type of adoptive cell transfer (ACT). This promising immunotherapy approach collects and uses a patient’s own immune cells to treat cancer.
As the name implies, the core of CAR T-cell therapy are T cells, a type of white blood cell responsible for protecting the body against infection and disease. Some cancer cells are able to avoid an immune response by using surface proteins that trick T cells into leaving them alone.
CAR T-cell therapy gets around this deception and boosts the immune response in two ways:
- T cells are genetically modified to produce receptors on their surface called chimeric antigen receptors, or CARs. These synthetic molecules allow T cells to recognize and latch on to specific proteins (antigens) on cancer cells and initiate an attack.
- Millions of these engineered CAR T cells are grown in a laboratory and then given to the patient by infusion.
In 2017, the U.S. Food and Drug Administration approved CAR T-cell therapies for children with acute lymphoblastic leukemia and adults with advanced lymphomas. Clinical trials testing CAR T-cell therapy on mesothelioma and other solid tumor cancers are underway.
How Does CAR T-Cell Therapy Work?
CAR T-cell therapy works by increasing the number of T cells capable of recognizing cancer cells. This boosts the immune system’s offense to fight cancer.
The engineered CAR T cells are like a living drug. The chimeric antigen receptors added to the T cells are synthetic molecules that don’t exist naturally. This allows the modified T cells to target cancer cells and overcome the cancer’s defense.
Process of CAR T-Cell Therapy
- Blood is drawn from the patient to get T cells. The blood flows through a tube to an apheresis machine that removes T cells and other white blood cells. The rest of the blood is returned to the patient.
- T cells are sent to a lab. Using a disarmed virus, the CARs are added to the extracted T cells.
- Engineered CAR T cells are multiplied until there are millions. They are then frozen and sent to the hospital or medical center where the patient will be treated.
- The patient typically undergoes a chemotherapy regimen to make space for the large number of modified T cells.
- CAR T cells are put into the patient’s bloodstream and continue to multiply.
- The added CARs are attracted to antigens on the surface of cancer cells, allowing the T cells to bind to cancer cells and kill them.
CAR T cells may remain in the body months after the infusion to prevent cancer recurrence.
Possible Side Effects from CAR T-Cell Therapy
The most common side effect of CAR T-cell therapy is cytokine release syndrome (CRS).
Cytokines are chemical messengers that help T cells carry out their functions. These are produced when the CAR T cells multiply in the body.
The rapid release of cytokines can cause CRS. Symptoms of CRS range from mild flu-like symptoms (fever, fatigue, chills) to more severe symptoms such as dangerously low blood pressure, rapid heart rate, internal bleeding and heart failure.
CRS can be difficult to measure and manage because it means the CAR T-cell therapy is working. This is called an on-target effect. Patients with extensive disease typically experience more severe CRS symptoms.
CRS can be fatal, but most symptoms can be managed with standard supportive therapies such as tocilizumab.
CAR T-Cell Therapy Research for Mesothelioma
Research for CAR T-cell therapies is largely focused on blood cancers, but recent studies are evaluating this treatment for patients with solid tumors, including malignant mesothelioma.
The biggest challenge facing researchers is finding suitable antigens to target on solid tumors.
Fortunately for mesothelioma patients, one of the antigens investigators are targeting in clinical trials is mesothelin, a protein overexpressed in most mesotheliomas.
A 2021 study of anti-mesothelin CAR T-cell therapy reported stable disease in 11 out of 15 patients 28 days after treatment. The study noted that five of those patients developed disease progression at a later point.
A phase I/II trial at the National Cancer Institute in Bethesda, Maryland, is evaluating the safety of a CAR T-cell therapy against mesothelin in patients with cancer that cannot be removed by surgery.
“The purpose of this study is to determine a safe number of these cells to infuse and to see if these tumor-fighting cells (anti-mesothelin cells) cause metastatic cancer tumors to shrink,” the objective of the clinical trial reads.
Other potential targets being studied for mesothelioma include:
- Vascular endothelial growth factor receptor 2 (VEGFR2) CAR
- Pan-ErbB “T4” CAR
- 5T4 CAR
- Chondroitin sulfate proteoglycan CARs
However, early reports from the trial have not shown the same success CAR T-cell therapy has had with blood cancer. The anti-mesothelin trial is expected to run through 2029.
Researchers at the University of Pennsylvania Perelman School of Medicine authored a 2017 study listing potential targets for CAR T-cell therapy for malignant pleural mesothelioma (MPM) and strategies for using the treatment with other forms of immunotherapy.
In addition to mesothelin, the study identifies fibroblast activation protein (FAP) as a potential target. FAP is overexpressed in all three subtypes of MPM.
“The results of these trials will be used to iteratively improve the next series of trials, eventually leading, it is hoped, to adoptive T cell transfer as an important part of the MPM therapeutic armamentarium,” the study concluded.