Cancer is one of the leading causes of death worldwide. Over the years, many conventional cytotoxic methods for tumor diseases have been developed. However, because of their limited effectiveness based on the heterogeneity of cancer cells, scientists are always looking for treatments with improved results, such as immunotherapy that utilizes and enhances the normal ability of the patient`s immune system. Chimeric antigen receptor (CAR) T cell therapy involves genetic modification of a patient`s own T cells to express a CAR specific for a tumor antigen, which is then expanded in vitro and returned to the patient.
Currently, FDA-approved CAR T-cell therapy products are only used in adult B-cell non-Hodgkin`s lymphoma or childhood acute lymphocytic leukemia that have passed two unsuccessful standard treatments. But now clinical trials are beginning to evaluate CAR T-cell therapy as first-line or second-line treatment for adult lymphoma and childhood acute lymphoblastic leukemia.
How Car-T Therapy Works
CAR therapy is both cell therapy, gene therapy, and immunotherapy. CAR-T therapy involves infusion of engineered T cells that carry a chimeric antigen receptor (CAR) on the cell membrane. The external domain of this receptor is designed to recognize specific molecules on tumor cells. When this happens, the molecule`s internal signaling domain is activated, which stimulates T cells to attack cancer cells. There are several generations of CARs that carry additional internal domains that can further enhance the immune response against programmed targets. The most common procedure for CAR-T cell therapy is to extract T cells from the patient being treated. This process is called leukocyte isolation. T cells are then genetically modified to express CAR molecules and expand. Finally, they are injected back into the patient, ready to fight the tumor.
How CAR-T cells Revolutionize Cancer Treatment
Checkpoint inhibitor-based immunotherapy has been very successful in certain cancer patient populations. Checkpoint inhibitors block the mechanism that tumor cells use to evade immune cells. CAR-T cell-based immunotherapy is a step forward, transforming the T cells themselves to enhance the natural immune response to specific tumor antigens. CAR-T clinical trials have shown a huge remission rate of 94% in severe forms of blood cancer. This is particularly impressive considering that cancer patients recruited by most CAR-T clinical trials do not respond to many, if not all, of the other available therapies. Although these results have satisfied the expectations of patients and investors, this new cancer treatment is powerful, however, there are serious risks that need to be considered before starting treatment.
Risks of CAR T-cell Therapy
CAR-T cells are actually associated with severe and even fatal side effects such as neurotoxicity and cytokine release syndrome. In 2016, several companies reported multiple deaths in advanced clinical trials of CAR-T therapy. What happens makes researchers realize that the technology might not be as perfect as they originally expected. CRS is caused when CAR T cells produce a large number of inflammatory molecules. And CRS can cause long-term fever, low blood pressure, difficulty breathing, and problems with different organs.
CAR T-cell therapy can also cause neurological issues. These may include problems with memorizing words, difficulty speaking, alertness, less delirium, hallucinations, seizures, and coma. In many patients, these problems will disappear on their own within a few days, but some have died as a result of these problems.
In addition, for both non-Hodgkin`s lymphoma treatments, study participants observed severe side effects. About a quarter of patients taking tesagiline microcells experienced severe CRS, and one in ten patients had neurological disease. Axicabtagene ciloleucel causes severe CRS in about 1 in 10 patients, and nearly 3 in 10 patients develop neurological disease.
Prospects and Future Development of CAR-T Therapy
Despite severe side effects and several deaths in clinical trials, some people believe that CAR-T therapy is worth the risk for patients who do not respond to other available therapies. Currently, CAR-T developers are already developing next-generation CAR T cells that are safer for patients. Another strategy is to combine CAR T cells with other types of cancer immunotherapy. For example, by injecting them with checkpoint inhibitors that block cancer`s defenses against T cells, they can improve their efficacy and reduce their dosage. Further optimizing the range of CAR-T cell design and delivery raises hope for more patients with malignant tumors and heralds a new era in cancer treatment.
