Cancer remains one of the biggest challenges in medicine. By 2040, the number of new cancer cases diagnosed worldwide each year is expected to rise to 29.5 million. Over the past years, there has been an expansion of exciting research offering a potential solution to cancer using immunotherapy, an approach referred to as the “fifth pillar” of cancer treatment by many, which works by strengthening a patient’s immune system to detect and kill cancer cells. Through promising research and trials, CAR T-cell therapy – a branch of immunotherapy - is on the rise, employing genetic engineering techniques to create a technology that is revolutionising and transforming oncology.
What is cancer?
Cancer is an umbrella term for more than 100 types of diseases arising from genetic mutations in genes that control the growth and division of cells. Cancer cells can ignore signals in the body, enabling their rapid and continuous division, causing the formation of tumours. They are also able to ignore signals that induce apoptosis, a process used by the body to remove unneeded cells. Additionally, cancer cells can evade the immune system by avoiding detection, or simply switching off immune cells. Once the cancer cells break away from their original location, they can spread to different parts of the body. This is the point where the cancer becomes metastatic.
One of the biggest problems that increases the difficulty of cancer treatment is the uniqueness of each cancer as it is composed of its own special set of genetic mutations. This complexity can even extend to cases where different cells within the same tumour have different mutations. Therefore, treatment cannot be made with a “one size fits all” approach, as different cancers respond to different treatments, a difficulty further complicated by factors such as patient lifestyle or tumour physiology. Current treatments, including surgery, radiation therapy, chemotherapy and more, work by killing cancer cells, shrinking or removing tumours, or easing symptoms.
How does CAR T-cell therapy work?
CAR T-cell therapy is a rapidly emerging form of immunotherapy under the branch of adoptive cell transfer (ACT), an immunotherapy approach which uses the patient’s own immune cells to treat cancer. As the name suggests, CAR T-cell therapy focuses on genetically rewiring T cells, a type of lymphocyte originating from the bone marrow that is responsible for killing host cells that have been infected, activating immune cells and regulating the immune response.
The treatment starts with a process called apheresis. Blood is drawn from the patient and passed into a machine that separates and collects T cells. The remaining blood is returned to the body. Using a disarmed virus, DNA is introduced to the T cells, causing the production of chimeric antigen receptors (CARs) on their surfaces, proteins that enable T cells to recognise and attach to a specific antigen on their targeted tumour cells. Once T cells have been genetically engineered, an “expansion” of the modified cells takes place, a process carefully monitored to ensure a sufficient number of T cells is produced to eventually be infused into the patient. The engineered T cells continue to multiply in the body, performing their programmed job of recognizing and killing cancer cells with specific antigens.
Through trials, many labs have refined and improved such a technological process greatly and are able to produce a batch of CAR T cells in as little as seven days or less, demonstrating impressive efficiency.
Acute lymphoblastic leukemia (ALL) is one of the most common cancers in children and a recurrence of ALL is the leading cause of death from childhood cancer. Trials utilizing CAR T cells have been carried out in children and young adults with relapsing ALL or were not responding to their treatment. In one of the earlier trials (led by Dr. Grupp of the Children’s Hospital of Philadelphia), CD19 (an antigen expressed on B cells) was used in creating CD19-targeted CAR T cells. Out of the 30 patients involved in the trial, all signs of cancer disappeared in 27, with many displaying no signs of recurrence after the treatment.
The success from these trials became the stepping-stones of a larger trial also using CD19-targeted T cells, which successfully produced Kymriah™, “the first gene therapy available in the United States” approved by the FDA in August 2017. Further research has shown encouraging results in treating lymphomas with CD19-targeted CAR T cells, increasing the excitement around the potential of CAR T cell therapy to treat various types of cancers.
Patients who have undergone CAR T cell therapy, however, are at risk of several side effects. They could develop cytokine release syndrome (CRS), a condition where the immune system is over-activated. Cytokines are chemical messengers released by T cells that stimulate and direct immune responses. CRS causes a rapid large-scale release of cytokines into the bloodstream which can cause dangerously high fevers, drops in blood pressure, and even organ failure in severe cases.
CAR-T-cell-related encephalopathy syndrome (CRES) is also a potentially fatal side effect, ranging from mild confusion to cerebral oedema, the swelling of the brain which carries life-threatening implications for the patient.
The future of CAR T cell therapy
The groundbreaking medical breakthrough of CAR T cell therapy has stimulated an explosion of research and trials around the world.
“I think we’re going to see dramatic progress and push the boundaries of what many people thought was possible with these adoptive cell transfer-based treatments,” Steven Rosenberg, an immunotherapy pioneer, said.
Scientists are now looking towards creating off-the-shelf CAR T-cell therapies, while some companies are already testing this novel approach, aiming to create treatment readily available for use. However, hospitals that provide and deliver this treatment will need to establish multidisciplinary teams to tackle the potential complications that may arise. Nevertheless, this exciting discovery positions scientists one step closer to finding a solution to such a devastating disease, and is a prominent example of the vast potential of genetic engineering.
Picture reference: Diagram showing Car T cell therapy.png