When the immune system is functioning normally, immune cells move around the body looking for things that don’t belong, like bacteria and viruses. These immune cells search for invaders using “receptors,” which can be thought of as antennae or feelers. When receptors find invaders in the body, special immune cells come in to destroy them. These special cells are called cytotoxic T cells.
Unfortunately, cancer cells are often able to hide from immune cells, which is why the cancer cells can grow out of control. Immunotherapy is a cancer treatment intended to make the body’s immune system able to detect and destroy cancer cells. Immune checkpoint inhibitors have been a successful immunotherapy approach because it pushes the immune system into high gear to fight cancer.
CAR T-cell therapy, however, is different. It is a type of immunotherapy called “adoptive cell immunotherapy.” As ASCO President Bruce E. Johnson, MD, FASCO, describes it, this technique “allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body.”
In CAR T-cell therapy, a person’s T cells are removed and taken to a laboratory. The T cells are genetically changed so they will attack cancer cells. These CAR T cells are grown in large numbers and then injected into the patient. One of the remarkable things about this treatment is that it is a “living therapy.” CAR T cells typically have to be injected only once, because they go on to multiply in the body. CAR T cells continue fighting the cancer in the patient’s body, and their effectiveness may even grow over time.
Emily Emily, the first child to be cured with Chimeric antigen receptor T (CART) cell therapy, was received by President Obama in 2016. This interview made more people began to understand CART cell therapy and gave hope to more leukemia patients to survive.
Despite the success of CAR T cell therapy, this intervention carries the risk of serious side effects. These include neurotoxicity, which can lead to headaches, confusion and madness, as well as other neurological changes. But there is less awareness to them. A team at Brigham and Women’s HospiTal recently classified the neurological symptoms of patients treated with CAR-T cells to better understand their neurotoxic side effects. Although neurological symptoms are common (77% of patients have at least one symptom), they are also temporary. The findings were published in the journal Brain.
“The mechanism of CAR T cell-associated neurotoxicity is unclear and the symptoms are difficult to predict,” said Daniel Rubin, MD, Ph.D., the first author of the study. “We conducted this study to better define the specific neurological symptoms experienced by patients after CAR T cell therapy.”
To clarify the clinical signs of CAR-T-related neurotoxicity, the team was admitted to Dana-Farber/Brigham and Women’s Cancer between 2015 and 2018 at the Dana-Farber/Brigham and Women’s Cancer Center. An observational cohort study was performed in 100 lymphoma patients with CAR T-cell Therapy. The team evaluated symptoms from the start of CAR T cell therapy infusion to two months after infusion. In addition, all diagnostic assessments, including laboratory tests and imaging scans, were reviewed.
“We shared some clinical cases of early treatment. From a neurological point of view, these cases are very serious and unusual,” said neuroscientist Henrikas VaiTkevicius, MD. “This has spurred our interest in working with the oncology and T-cell treatment teams, allowing us to prospectively evaluate most patients rather than retrospectively.”
Their findings reveal the prevalence of neurological symptoms after CAR-T treatment. The most common symptom is encephalopathy, a brain disorder that causes confusion, headache, tremors, weakness, and language problems. Importantly, these effects are mostly reversible, and the symptoms almost always disappear over time.
In addition, researchers found a unique pattern of activity or inactivity in their research. Treatment-related neurological dysfunction often originates from areas where metabolic function appears to be inactive. This finding is important for the clinical evaluation of neurotoxicity and the application of imaging.
Rubin said: “Although neurological symptoms are common, imaging studies such as MRI, which is the basis of neurological diagnosis, are almost always normal. In contrast, diagnostic studies that directly assess neuronal function, such as electroencephalography (EEG), are more straightforward. And positron tomography (PET), which reliably detects and predicts neurological dysfunction.”
Next, the researchers will establish and validate a model to more accurately assess and diagnose CAR-T-related neurotoxicity.
- Fraietta JA,Lacey SF, Orlando EA,et al.Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.Nat Med. 2018,24(5):563-571
- Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 2016;127: 3312-3320；
- Carl H. June and Michel Sadelain. Chimeric Antigen Receptor Therapy. N Engl J Med. 2018, 6.379,1: 64-74；
- Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 2016;127:1117-1127；
- Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol 2017;35:1803-1813；
- Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 2017;129: 1039-1041；
- Golubovskaya V, Wu LJ.Different Subsets of T Cells, Memory, Effector Functions, and CAR-TImmunotherapy. Cancers 2016,15;8(3): E36；