“CAR T-cell therapy can be a double-edged sword. While highly effective, patients can become seriously ill in the first 10 days after infusion and so it is critical that this treatment be used only by medical teams capable of dealing with the side effects, should they occur.”
- Stephen P. Hunger, MD, ASCO Expert
Twenty-five years in the making, the concept of redesigning T cells to eliminate cancer is still in its infancy. What will it take to bring CAR T-cell technology to routine cancer care? A key challenge to implementing wider use is managing the side effects patients often experience. While more work lies ahead, recent research provides clues on how to make this treatment approach safer.
Cytokine Release Syndrome
Although it is only a one-time treatment, the side effects of CAR T-cell therapy can be serious. The most common and most dangerous side effect of this “living therapy” can occur in a matter of hours after injection of CAR T cells. Upon entering the body, CAR T cells whip up a “storm” of inflammatory molecules called cytokines. This response, known as cytokine release syndrome (CRS), is characterized by a unique set of symptoms: prolonged fever, low blood pressure, difficulty breathing, and problems with multiple organs. Severe CRS may require intensive medical care, such as use of a ventilator or “pressors” to increase blood pressure, and seizure medication.
In clinical trials of CAR T-cell therapy for patients with acute lymphoblastic leukemia (ALL), the rates of severe CRS ranged from 23% to 46%. Fortunately, the symptoms of CRS are fully reversible in most cases. In one study, 2 out of 97 patients with ALL who received CAR T cells died of CRS. Most patients, however, experience mild to moderate CRS, which is manageable with supportive care.1,2
There are two effective treatments for CRS: corticosteroids and tocilizumab, which blocks the receptor for the cytokine IL-6. Of the two, tocilizumab is more widely used because it quickly lessens the symptoms of CRS without harming CAR T cells. In contrast, corticosteroids can interfere with T cell growth, thereby shortening cancer remissions, and do not work as well as tocilizumab for controlling CRS.
It is difficult to predict which patients will experience CRS and to what degree, but it is clear that patients with high leukemia burden are at greater risk for severe CRS.3 A recent study uncovered that increased blood concentrations of certain cytokines -- C-reactive protein and ferritin -- were strongly associated with development of CRS. These insights will help inform development of laboratory tests to predict which patients are at risk of becoming critically ill following infusion of CAR T cells.4
There is significant interest in discovering ways to effectively identify patients who are at high risk for CRS so they can be treated with tocilizumab early to prevent severe CRS. Another therapy under consideration for CRS treatment is ibrutinib, a drug that blocks signaling through the B-cell receptor in chronic lymphocytic leukemia (CLL) and other mature B-cell cancers.5
Neurologic side effects are frequently reported in clinical trials of CAR T-cell therapy. These effects include word recall problems, difficulty speaking, reduction of alertness, delirium, hallucinations, seizures, and coma. In clinical trials of CAR T-cell therapy in patients with ALL, the rates of severe neurologic complications ranged from 35% to 50%. In most patients, neurologic problems resolved on their own within a few days without long-term consequences. More severe symptoms were treated with high-dose steroids and seizure medication.1 Several deaths due to neurologic side effects, such as brain swelling, have occurred following CAR T-cell therapy.6
It is not yet clear how and why CAR T cells (and other T-cell activating therapies) trigger neurologic symptoms, but they do not appear to correlate with the severity of CRS, nor can they be prevented by tocilizumab. More research is needed to uncover possible predictors and treatments for neurologic side effects.
Collateral Damage to Healthy Cells With the Same Target
CAR T cells are smart in terms of sniffing out cancer cells with specific antigens, but if they encounter a healthy cell with the same molecule, they won’t be able to tell that it’s not a cancer cell and will destroy it. For instance, CD19 CAR T cells will attack both cancer cells and healthy B cells, as both have CD19 on the surface. This is concerning to researchers and physicians because healthy B cells are needed to maintain good health, as they produce infection-fighting antibodies. Fortunately, immunoglobulin (antibody) injections remedy the lack of healthy B cells for patients in whom CAR T cells persist for a long time. At the same time, depletion of healthy B cells is a good sign that the CD19 CAR T-cell therapy is working.
For CAR T cells targeting antigens other than CD19, however, the potential damage to healthy cells that have the same target as the cancer cells has been a major challenge. For example, an immune attack on healthy cells in vital organs, such as the heart and lungs, can be very dangerous.6 Finding a unique biomarker that is present on cancer cells and nowhere else in the body has proven to be difficult. Research is underway to focus on developing screening tests to help predict whether a particular CAR T-cell therapy poses a threat for autoimmune disease.
Efforts to Improve Safety
At the same time, we need a more sophisticated approach to controlling the immune system, which may involve manipulation of more than one type of T cell. For instance, there are early indications that genetically engineering so-called “regulatory T cells” might help mitigate autoimmune reactions.
In recent years, researchers have proposed different molecular techniques to improve the safety of CAR T-cell therapy.7,8 For example, certain new CAR T-cell designs come equipped with “molecular suicide switches,” which can be turned on in the body by specific chemicals. This approach could allow doctors to direct the CAR T cells to self-destruct in cases of severe adverse effects.
The emerging “on-switch” and “transient” CAR T-cell designs allow for even finer control of CAR T-cell activity. These designs include a molecular switch that acts like a remote control, allowing doctors to turn on inactive CAR T cells in the patient’s body using specific drugs. When the drugs are no longer present in the body, the CAR T cells become inactive again.
Finally, to lessen damage to healthy cells with the same target as the cancer cells, scientists have proposed dual-receptor CARs, which necessitate that CARs recognize two different antigens on cancer cells for full activation. As healthy cells typically have only one of the antigens on their surface, the CAR T cells would be less effective against them.
Part III of this series delves into other challenges and possible solutions that may help bring CAR T cells into routine cancer care. Look out for this next installment in the coming weeks.
1. Davila ML, Brentjens RJ: CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol 14:802-808, 2016
2. Fitzgerald JC, Weiss SL, Maude SL, et al: Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia. Crit Care Med 45:e124-e131, 2017
3. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25, 2014
4. Teachey DT, Lacey SF, Shaw PA, et al: Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov 6:664-79, 2016
5. Ruella M, Kenderian SS, Shestova O, et al: Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31:246-248, 2017
6. Bedoya F, Frigault MJ, Maus MV: The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy. Molecular Therapy 25:314-320, 2017
7. Zhang E, Xu H: A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy. J Hematol Oncol 10:1, 2017
8. Lim WA, June CH: The Principles of Engineering Immune Cells to Treat Cancer. Cell 168:724-740, 2017