UCSF, St. Jude Identify Key Culprit Driving Treatment Resistance in Deadly Immune Disorder – Innovita Research

UCSF, St. Jude Identify Key Culprit Driving Treatment Resistance in Deadly Immune Disorder

A new study by researchers at UCSF Benioff Children’s Hospitals and St. Jude Children’s Research Hospital have identified what they believe to be a key reason behind patients’ treatment-resistance in the rare inflammatory disorder HLH. The finding could offer additional insights into other immune conditions, including a type of childhood leukemia and the severe inflammation response in some children with COVID-19.

The study, which aimed to understand why many HLH patients fail to respond to standard treatment, found that interleukin-2 – a type of immune system protein known as a cytokine – plays a prominent role in treatment resistance.

HLH, or hemophagocytic lymphohistiocytosis, is a severe, systemic inflammatory condition that affects 1 in 50,000 to 100,000 people – mainly children – and is caused by white blood cells attacking other blood cells and collecting in the spleen and liver, prompting both organs to enlarge. The condition is usually treated with the anti-inflammatory steroid dexamethasone and the chemotherapy etoposide. However, many patients either fail to respond to this regimen or relapse. Currently, approximately 40 percent of children with HLH die from complications of hyper inflammation, despite treatment.

The researchers’ work in human and mouse cells and mouse models determined that of all the cytokines that are elevated in HLH, interleukin-2 and related cytokines were critically important to driving resistance to dexamethasone. Interleukin-2 is produced by activated T-cells and promotes their survival. The researchers showed that by blocking the effects of interleukin-2, the T-cells can be re-sensitized to and destroyed by dexamethasone.

Integral to their research, which published in the journal Blood is the role of Janus kinases, which are signaling molecules that become activated when the cytokines bind to the receptors on the surface of cells.

Co-senior author Michelle Hermiston, MD, Ph.D., from the UCSF Department of Pediatrics (Hematology/Oncology) said that lessons from previous studies on children with leukemia, who are also treated with dexamethasone, were applied to the team’s research on HLH. “Like in leukemia, we were able to show that a specific cytokine signaling through the JAK pathway could promote resistance to treatment,” she said.

Drug for Bone Marrow Disorders May Boost Survival

Earlier research by co-senior author Kim Nichols, MD, of St. Jude Oncology, had revealed that ruxolitinib, a JAK inhibitor prescribed for patients with bone marrow disorders, had a positive effect on mouse-models of HLH. The focus of the current study was to identify the cytokine that was the key culprit in dexamethasone resistance, she said.

The combination of dexamethasone and ruxolitinib was found to be more effective in these animal studies than either agent alone. St. Jude has developed a clinical trial that will take place at 12 sites, including UCSF, to test this new protocol.

“We are hopeful that by adding JAK inhibition to their therapy, we can improve outcomes for patients,” said Hermiston. “It may have important implications for other inflammatory diseases. This includes children with a type of leukemia called T-ALL and individuals with severe Covid-19, where increased inflammation appears to contribute significantly to poor outcomes.”

Source: UCSF