Chimeric Antigen Receptor T-cell (CAR T-cell) therapy has been used and is fast becoming a treatment of choice for patients suffering from blood cancers like leukemia and lymphoma.
CAR T-cell therapy involves modifying a patient's T-cells, a type of white blood cell, to express chimeric antigen receptors (CARs) on their surface. These CARs are engineered to recognize specific proteins, or antigens, on the surface of cancer cells. When these cells are infused back into the patient, they locate and bind to the cancer cells, and trigger an immune response that leads to the destruction of the cancer cells. So, this therapy harnesses the body's own immune system to kill cancer cells.
After the therapy has shown remarkable success in treating blood cancers, scientists worldwide are exploring if CAR T-cell therapy can become a potent weapon against solid tumours as well.
Solid tumours, however, have different physiology. These tumours develop in organs such as the lungs, breast, and abdomen. Most of the solid tumours are surrounded by a complex consisting of cells, blood vessels, and extracellular matrix components, which, can suppress immune responses and act as a physical barrier. It makes it difficult for CAR T-cells to infiltrate the tumour and exert their effects.
Moreover, solid tumours are often heterogeneous, meaning, they contain a diverse range of cancer cells with varying characteristics. This heterogeneity can make it challenging for CARs to identify an antigen that is consistently expressed across all cancer cells within the tumour.
Interestingly, ongoing research is trying to find ways to overcome various challenges associated with treating solid tumours using CAR T-cell therapy. For example, to address the issue of tumour heterogeneity and antigen escape, researchers are developing CAR T-cells that can target multiple antigens simultaneously. By incorporating multiple CARs into a single T-cell or by using a universal CAR that can be redirected to different antigens, we are hoping to effectively target the tumour. In fact, we are very close to develop such CARs to fight stubborn blood cancers.
Besides, researchers are exploring ways to enhance the persistence of CAR T-cells in patient’s body by modifying them to resist exhaustion. A prolonged stay may increase the effectiveness of the therapy. Also, engineering CAR T-cells to be able to secrete cytokines like IL-12 can help modulate the tumour microenvironment, making it more resistant to an immune attack.
Work is being done to improve the delivery of the CAR T-cells. If this therapy can be directly delivered to the tumour site through regional injections rather than through systemic infusion, it can be more effective and it will also reduce the risk of it attacking healthy tissues.
Another interesting step to make these therapies even safer would be to be able to turn off or eliminate the CAR T-cells if they cause severe side-effects. Researchers have developed what are called safety switches, which provide an additional layer of control over the therapy, improving its safety profile, especially in the treatment of solid tumours.
Despite the challenges, there have been promising results in preclinical and early clinical studies of CAR T-cell therapy for solid tumours. For instance, CAR T-cells targeting HER2, a protein overexpressed in some breast and gastric cancers, have shown encouraging responses in preclinical models. Similarly, CAR T-cells targeting mesothelin, an antigen expressed in mesothelioma and pancreatic cancer, are being tested in clinical trials, with some patients experiencing tumour shrinkage and prolonged disease control.
Advances in gene editing technologies like CRISPR or combining CAR T-cell therapy with other immunotherapies are constantly improving its efficacy and safety in solid tumours.
The author is a pediatric hematologist and oncologist with an active interest in cell and gene therapy.
