Assay Helps Predict Adverse Cytokine Response to Rituximab in Leukemia Patients

Leukaemia blood cells, SEM
Leukaemia blood cells. Coloured scanning electron micrograph (SEM) of B lymphocyte white blood cells (round) from a patient with leukaemia. Magnification: x5000 when printed 10 centimetres wide.

Researchers at Uppsala University in Sweden have developed an assay could predicted how likely patients were to experience cytokine release syndrome—the excessive immune reaction seen in some patients from receiving immunotherapies—when receiving the monoclonal antibody rituximab and other similar therapies.

Rituximab is an effective therapy used to treat a range of B-cell cancers and autoimmune disorders like rheumatoid arthritis. It works by binding to CD20 receptors, which are found mostly on the surface of B immune cells, and then killing the cells it binds to.

Although it can be very effective, rituximab can trigger the release of cytokines in some patients resulting in cytokine release syndrome. While this can be mild, just resulting in nausea and fever, it can also be life threatening.

“This unpredictability is a major challenge, but the results from our study show that our analysis method can provide patient-specific information and thus become an important tool for the whole immunotherapy field if we are able to understand the individual’s specific response to a given antibody-based therapy,” says Sara Mangsbo, Ph.D., a senior researcher at Uppsala University who led the study.

In this study, which was published in the journal International Immunopharmacology, Mangsbo and team tested blood from six patients with chronic lymphoblastic leukemia (not currently undergoing treatment) and five age-matched, healthy controls to assess the impact of rituximab infusion.

The researchers used a special assay comprised of a moving, whole blood loop system, to simulate the effects of an infusion of the drug into the patient’s blood stream. This technology has previously been used to predict cytokine release in healthy blood and also to study the impact of donor cells on recipient blood in transplant patients.

The results observed varied considerably between the two groups. The blood from healthy volunteers showed a reduction in B cells of up to 12%, but nothing else. Cytokine levels were normal. However, in those with leukemia there was a greater reduction in B cells of 30-45%, but also changes in other immune cells linked with cytokine release syndrome. It varied between individuals but increases in the cytokines interferon gamma, tumor necrosis factor alpha, and interleukin 6 and 8 were all observed.

Blood from three of the leukemia patients showed signs of cytokine release syndrome in the assay and indeed, when the patients went on to receive treatment with rituximab or obinutuzumab they all showed signs of having the syndrome.

“Rituximab is used to treat a range of diseases in which B cells are malignant or growing out of control. The monoclonal antibody binds to the CD20 protein expressed on the B cell and draws natural killer cells, a part of the immune system, to the site which then help to kill the B cell. The action of Rituximab is specific with few side effects, but when it binds to B cells it can also activate proteins in our blood that signal danger,” explains Mangsbo.

“More extensive studies in specific patient groups are needed now to increase our understanding of how individual immune systems will react to both rituximab and other monoclonal antibodies. In the long term, we hope to take the method all the way to clinical trials as well as to the healthcare system in order to provide a better answer to which patients will respond well to specific immunotherapy treatments.”

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