One of the most important questions that immuno-oncologists will tackle in the coming years is figuring out where chimeric antigen receptor (CAR) T-cell therapy will fit into the larger picture. Academic centers across the country have been using this technology to successfully treat patients, but adapting this complicated system to a community setting introduces a number of logistical issues. CAR T-cell therapy is a form of adoptive cell transfer (ACT), meaning that a patient’s own immune cells are engineered to attack tumors. ACT has achieved some positive results in patients with advanced cancers that are difficult to treat, but the process of creating such therapies is both costly and time-consuming.5
How CAR T-Cell Therapy Works
Some people think of CAR T-cell therapy as a type of living drug. A patient’s T cells are engineered to produce special receptors along their surface that bind to antigens on tumor cells. These so-called chimeric antigen receptors allow naturally occurring immune cells to target tumors when they previously were unable to do so.
The entire process starts with T cells collected directly from patients through a process called apheresis. Blood is withdrawn from the veins and then separated into its component parts. The blood components not needed for the
therapy are returned to the body immediately. Once T cells have been isolated, they undergo genetic engineering that causes them to express CARs. The specific CARs expressed depend on the composition of the tumor. Ultimately, the engineered cells need to bind to the targeted tumor.
Once CAR T cells are produced, they are allowed to multiply in a laboratory. The cells divide until there are many millions of them. Then, the cells are frozen and returned to the treatment center so that they can be reintroduced into a patient’s body. Patients typically receive a course of chemotherapy before receiving the cells. Once reintroduced into the body, CAR T cells multiply naturally so that they can launch an all-out attack on the tumor, which they recognize by the targeted surface antigen.
The major benefit of CAR T-cell therapy is that the CAR T cells stay in the body for a very long time following the infusion. As a result, they can continue to attack cancer cells whenever they form, which guards against a recurrence. Many researchers believe that this approach to immunotherapy has a greater likelihood of achieving long-term remission.
The Applications of CAR T-Cell Therapy
The results from early CAR T-cell trials have had some fairly positive outcomes, especially for blood cancer. Patients with acute lymphoblastic leukemia (ALL) who have relapsed after chemotherapy or a stem cell transplant may be able to turn to the therapy as a legitimate option. Some studies showed a 90 percent remission rate among children and adults with ALL who relapsed multiple times or who did not respond to traditional therapy. Promising results have also been achieved with CAR T-cell therapy in chronic lymphocytic leukemia, some forms of non-Hodgkin lymphoma, and multiple myeloma.
While the results are promising, the patients involved have only been followed for a short amount of time, and more long-term data is required for real conclusions about the length of their responses. Many more large-sample studies are needed to help researchers understand the therapy, including ways to reduce toxicity and improve efficacy.
The Side Effects of CAR T-Cell Therapy
Researchers have found some serious side effects with the use of CAR T-cell therapy, such as cytokine-release syndrome (CRS). The syndrome, which results from T-cell activation, is an indication of a positive response to CAR T-cell therapy. However, large amounts of cytokines can lower blood pressure, cause high fever, and make it difficult for the lungs to oxygenate blood. Delirium, confusion, and seizure can also result. Cytokines are chemical messengers that help T cells kill cancerous cells, so they are critical for the treatment to work. However, when cytokines are released rapidly and in massive quantities, symptoms need to be monitored closely so that patients can be treated before the situation becomes critical.
Another serious issue is B-cell aplasia. If CAR T-cell therapy targets antigens on the surface of B-cells, they will destroy both healthy and cancer cells. The absence of healthy B-cells inhibits the body’s ability to produce antibodies and to protect against infection. However, intravenous immunoglobulin can be used to prevent infection, and long-term aplasia has not been documented clinically.
Tumor lysis syndrome may also occur with CAR T-cell therapy. This syndrome refers to a group of metabolic complications that occur when dying cells break down after the onset of treatment. Patients may not experience symptoms for a month or more after treatment. While complications can be managed through standard therapies, they can prove life threatening if left unchecked.
As more clinical trials are conducted, researchers will have a better idea of how to prevent these side effects. For example, researchers in one study noticed that patients who had the most severe reactions had high levels of the IL-6, a cytokine emitted by macrophages and T cells as a result of inflammation, so they used etanercept and tocilizumab, two drugs that block IL-6 activity.