2017 marks a breakthrough year for science and medicine alike, as it holds the distinction as the year in which the very first gene therapy was approved by the United States Food and Drug Administration (FDA). The result of decades of research and clinical trials, the approved gene therapy, referred to as chimeric antigen receptor (CAR) T cell therapy, has brought hope of long-term remissions and potential cure for some patients with otherwise incurable leukemia and lymphoma.
Although CAR T cell therapy itself is still in nascent stages and remains a far cry from being a cure-all for cancer, its approval has been hailed as a watershed event – both for patients and for cancer research. The two approved CAR T-cell therapy agents, approved within a couple months of each other, have bolstered widespread morale within the cancer community and provided proof-of-principle in terms of transforming scientific concepts into effective clinical therapies.
What is CAR T-cell Therapy?
In essence, CAR T cell therapy is a type of gene therapy that modifies a patient’s own T cells (a type of immune cell) to detect and kill the patient’s cancer cells. It is unique in comparison to other types of available immune therapies for cancer, in that the patient’s own T cells are the actual treatment; no other medications are used as an active component of therapy. Importantly, long-term results may be achieved with just one infusion.
The process involves removal of T cells from the patient’s blood to undergo genetic engineering outside of the body, which includes several steps:
- First, a patient’s blood is collected from a vein in the arm. The blood flows through a tube to a machine that removes and collects the T cells, and the rest of the blood is returned into the patient’s body.
- The collected T cells are sent to a laboratory where they are genetically modified, with the use of an inactive virus, to produce specific proteins on their surface. These proteins are called chimeric antigen receptors (CARs).
- The CARs are important because they enable the T cells to recognize and bind to specific proteins detected on the surface of the patient’s cancer cells, known as antigens.
- The genetically modified T cells, now referred to as CAR T cells, are multiplied in the laboratory into the hundreds of millions.
- The CAR T cells are then sent from the laboratory to the treating hospital where they are infused back into the patient’s body through a vein in the arm.
- Prior to infusion, the patient undergoes one round of a chemotherapy regimen to reduce the amount of cancer cells as well as other immune cells, which improves the body’s acceptance of the CAR T cells.
- Once infused, CAR T cells circulate throughout the patient’s body, and attach to cancer cells. This binding action stimulates an immune attack and destruction of the cancer cells.
The process spanning from the initial collection of a patient’s T cells to the infusion of the modified CAR T cells back into the patient takes approximately one week.
The “Living” Treatment
Since CAR T therapy exploits and harnesses critical properties of live T cells to fight cancer, it is sometimes referred to as a “living” treatment. Researchers continue to modify and improve the efficacy of the CAR T cells once they are infused back into the patients. For example, the extent of time the cells survive in circulation (called persistence) continues to be increased, as does as their ability to replicate in greater amounts in the body (called expansion) to enhance and sustain their anti-cancer activity.
CAR T Cell Therapy Approvals
The two CAR T cell therapy agents currently approved, Kymria and Yescart, are both for the treatment of cancers that originate in a type of immune cell, called a B-cell. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. However, both agents produce CAR T cells that bind to the CD19 protein; an antigen found on the surface of B- cells.
The first approved agent, Kymria™ (tisagenlecleucel), is for the treatment of children and young adults up to the age of 25 years with B-cell precursor acute lymphoblastic leukemia (ALL). ALL is the most common cancer, as well as the most common cause of cancer-related deaths, among children in the United States. The fact that the FDA first approved Kymriah™ for children and young adults is noteworthy and cause for celebration among childhood cancer advocates and physicians treating the disease. The typical FDA pattern is to first approve agents or therapies for adults, with approvals for use in children and youth often lagging far behind.
The second CAR T-cell therapy agent approved, Yescart™ (axicabtagene ciloleucel), is for the treatment of adults with diffuse large B-cell lymphoma (DLBCL).
Both Kymria and Yescart are approved for patients whose cancer has either never responded to standard therapies, or has returned following prior therapies. Patients with these types and stages of cancers were previously considered incurable and left with virtually no treatment options.
The final clinical trials prompting FDA approval of both Kymria and Yescart demonstrated rates between 50-80% of patients achieving a disappearance of their cancer, with some groups of patients demonstrating long-lasting responses to treatment. Data from these trials continues to be closely monitored for long-term results, as well as for gaining an understanding of patient and cancer characteristics associated with differing responses.
Due to potential side effects, CAR T cell therapy can only be administered in facilities that have received distinct certification demonstrating the ability to effectively manage these side effects. The facilities must demonstrate that each healthcare provider involved in the infusion process is qualified in safe procedures and risk management, and all necessary precautions must be available for immediate use.
One potentially fatal side effect of treatment, called cytokine release syndrome (CRS), is a response by the body to the activated CAR T cells. CRS can cause very high fevers, changes in blood pressure and flu-like symptoms if left untreated. In response to the dangers of CRS, the FDA has extended the approval of the drug Actemtra (tocilizumab) to treat severe or life-threatening CRS associated with CAR T cell therapy. Clinical trials have demonstrated that one or two doses of Actemtra resulted in complete resolution of severe CRS in nearly 70% of patients within two weeks.
Neurologic effects have also been associated in a small percentage of patients receiving CAR T cell therapy, as well as risk for infection. The risk for infection stems from the fact that the two CAR T agents target the CD19 antigen, which is found on the surface of both cancerous and healthy B-cells. Since B-cells are immune cells that contribute to fighting infection through the production of proteins called immunoglobulins, treatment with CAR T can reduce immunoglobulin levels to dangerously low numbers. Fortunately, immunoglobulins can be administered to patients to counteract this side effect.
The momentum created by the initial effectiveness of CAR T cell therapy has prompted robust research efforts within the contextual framework of “living therapy” to improve upon the initial results. Some examples of active research aligned with the CAR T therapy conceptual model include the following:
- Approval for treatment of different types of cancers affecting the blood and lymph system are being sought.
- CAR T cells that target one or multiple antigens, besides CD19, that are unique to different types of cancers are being developed and tested
- The effectiveness of two or more infusions of CAR T cells among patients who were partial or poor responders to the initial infusion, or those who experience a cancer recurrence, is being evaluated.
- Utilization of different types of genetic engineering or modification of a patient’s T cells, as well as utilization of cells other than T cells is also under investigation.
- CAR T therapy using a donor’s T cells is also being explored.
Researchers have also evaluated the use of CAR T cell therapy for solid tumors, such as breast and colon cancers. Although there has been some reported activity, solid tumors are very different than leukemia or lymphoma cancer cells, and pose many challenges for effective CAR T cell therapy. For example, many antigens unique to solid tumors reside inside the cancer cells, resulting in difficulties with the physical process of the CAR T cell binding to the cancer cell. This is in contrast to leukemia or lymphoma cells that tend to display antigens on the surface of the cells. Furthermore, the local environment directly surrounding a solid tumor, referred to as the microenvironment, is extremely complex and also poses difficulties for the CAR T cells to effectively reach the cancer cells. Nonetheless, researchers continue to explore the potential of CAR T cells in solid tumors, as well. However, the current fast-paced forward movement with CAR T cell therapy is focused on effective treatment of different types of leukemias and lymphomas.
CAR T cell therapy is another breakthrough in the era of precision medicine for the treatment of cancer. Although its future trajectory remains unknown, it has for now, restored the belief in the possibility that good-quality, long-term survival is truly attainable for some cancer patients who are otherwise left with no treatment options. Furthermore, it has renewed the resolve of researchers to continue in their quest of revolutionizing the treatment paradigm of cancer towards individualized therapy for every patient diagnosed with the disease.
- National Cancer Institute.(2017). CAR T-Cell Therapy Approved for Some Children and Young Adults with Leukemia. Retrieved from