New markers could identify patients most at risk of brain damage from CAR T cell immunotherapy

In collaboration with the Press Association
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Blood cancer patients most susceptible to a potentially fatal side effect of immunotherapy called neurotoxicity could be identified by looking for specific markers, according to a new US study.

The team, from the Fred Hutchinson Cancer Research Centre, identified a number of potential biomarkers that could help doctors identify those most at risk of damage to the brain or nervous system (neurotoxicity) after CAR T cell therapy.

"This type of research is important because the cause of the neurotoxicity in these patients is not well understood.” - Dr Martin Pule, Cancer Research UK

Researchers who led the study, published in Cancer Discovery, said that while the specific type of T cell therapy tested, called CD19 CAR T cell therapy, can be “highly effective” the side effects need to be better understood.

A small number of treatment-related deaths have been recorded in clinical trials using certain forms of immunotherapy with neurotoxicity as one of the major causes.

Analysing data from 133 patients with CD19 B-cell acute lymphoblastic leukaemia (ALL), non-Hodgkin lymphoma or chronic lymphocytic leukaemia (CLL) that had come back or become resistant to treatment. 

All were given CD19 CAR T cell therapy that was developed at the Fred Hutchinson Cancer Research Centre.

A similar treatment was recently approved in the US for certain patients with a particular type of blood cancer. 

Seven patients experienced ‘life threatening’ neurotoxicity with 4 patients dying 28 days after receiving the treatment.

Around 40 in 100 patients (53 patients) developed at least some side effects that affected the brain or nervous system.

The most common neurological side effect reported was delirium. Other forms of neurotoxicity included headaches, problems with speech and in 4 cases, seizure.

The team found that patients who had cytokine release syndrome, where the immune system becomes overactive, earlier on in treatment, had an increased risk of developing severe neurotoxicity.

"It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity,” said Dr. Kevin Hay, a lead author. But he added that understanding what causes a person with cytokine release syndrome to get neurotoxicity needs to be investigated further.

Injury to cells that line the blood vessels, called endothelial cells, was also identified as a potential marker that could warn doctors that a patient had a high risk of neurotoxicity during immunotherapy treatment.

Dr Martin Pule, a Cancer Research UK-funded CAR T cell expert from University College London, said: "This detailed analysis suggests that injury to the cells that line blood vessels could be behind the neurotoxicity that some patients experience after having CAR T cell therapy.”

He said the findings could lead to the development of accurate biomarkers for severe neurotoxicity, as well as strategies to reduce its severity.

The researchers now hope to use the data to develop a computer programme to help doctors identify patients most at risk of neurotoxicity. This could guide treatment such as altering the CAR T cell dose given to certain patients.

Experts say that when severe side effects occur during immunotherapy treatment, early intervention is crucial. These new indicators could reduce the amount of severe side effects and deaths already seen in certain CAR T cell trials.

"This type of research is important because the cause of the neurotoxicity in these patients is not well understood,” said Pule, highlighting that the occurrence of neurotoxicity is unpredictable and there is no clear way to treat it.

“Consequently, neurotoxicity has been the most troublesome clinical challenge with CAR T-cell therapy,” he added.

 

References

Gust, J. et al. (2017) Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discovery  doi: 10.1158/2159-8290.CD-17-0698