The Role of the Innate Immune System in Immune Dysregulation following CART
The job of the immune system is to fight infection. In healthy people the immune system also prevents cancer. Recently, new cancer treatments using the immune system have been made. These new treatments are called chimeric antigen receptor T-cells (CART). With CART, blood immune cells are collected from a patient. They are reprogrammed in a laboratory to fight cancer. The reprogrammed cells are given back to the patient. CART can cure some cancers. CART is particularly good at curing a type of cancer called B-cell acute lymphoblastic leukemia (B-ALL) in kids. CART work very well but they have side effects. Sometimes they make the immune system overactive. This is called cytokine release syndrome (CRS). CRS can make people very sick. CART can also cause side effects in the brain like seizures and coma. This is called immune effector cell associated neurotoxicity syndrome (ICANS). We do not understand why some people get CRS and ICANS. Understanding CRS and ICANS is important so we can prevent and treat them. Treating CRS and ICANS is essential to making sure CART can be used safely and cure more patients.
Project Goals:
The first goal of this project is to understand what is happening in the different cells of the immune system during CRS. Right now, we don’t understand which cells are responsible for starting CRS, and which cells are responsible for stopping it. We also don’t know what cells are making the proteins in the blood (cytokines) that are causing the immune system to be overactive. I will use a technique called single cell RNA sequencing that allows us to identify individual cells, and understand what proteins they are producing. This will help me understand why CRS is happening. Understanding the cell types that are overactive will help me identify better treatments.
The second goal of the project is to test new therapies for ICANS. In previous research that I’ve done I have found a protein, called IL-18, that goes up when patients have symptoms of ICANS. IL-18 has been studied in different diseases where children get sick from an overactive immune system. A drug already exists that blocks IL-18 and has previously been studied in children. In the second aim, I will test this drug in the laboratory to see if it can be used to treat ICANS. I also found a protein from a different part of the immune system, sc5b9, was higher in patients with ICANS. I will test blocking this protein to see if it can be used to treat ICANS. I will also test blocking both IL-18 and sc5b9.
2025 Update:
In the past year, we have looked at individual immune cells between patients who did and did not get CRS. We also look at the RNA that each of these individual cells make. We do this to understand what parts of the cell are “turned on”, so we can understand exactly what they’re doing to cause CRS. We have also looked at all the patients treated at our hospital who got ICANS. This is the biggest number of kids with ICANS ever looked at in one study. We found that the risk of ICANS was different for kids who had a small amount of B-ALL than for kids who had a large amount of B-ALL. With the support of ALSF, we are continuing to look in the laboratory at what causes CRS and ICANS.
