Neurological Side Effects from Cancer Immunotherapy May Be Linked to Low Levels of Phosphate in Blood
New findings may help physicians monitor for adverse reactions to immunotherapy and allow for early intervention.
A potentially severe side effect of an immunotherapy used for some types of cancer may be linked to low levels of phosphate in the patient’s blood, according to a study published in Cancer Immunology Research, a journal of the American Association for Cancer Research.
Chimeric antigen receptor (CAR) T-cell therapy helps the body’s own T cells, a type of immune cells, attack cancer cells. But in many patients, it triggers an adverse reaction known as immune effector cell-associated neurotoxicity syndrome, or ICANS. Symptoms include confusion, delirium, aphasia, impaired motor skills, and somnolence. In severe cases, life-threatening events, including seizures and coma, can occur.
A team led by Theodore Scott Nowicki, MD, PhD, assistant professor at the David Geffen School of Medicine of the University of California, Los Angeles, found that incidence and severity of ICANS were higher in patients who had low blood phosphate levels, a condition known as hypophosphatemia.
Nowicki explained that knowing of the link could help alert physicians to the development of ICANS and allow for early intervention.
“The treatment of ICANS is currently limited to supportive care and steroids, which are nonspecific and can have their own side effects,” he said. “Therefore, having the ability to predict the onset of ICANS would be a very helpful tool for clinicians.”
Nowicki and his team had previously observed a marked drop of phosphate levels in the blood of patients receiving CAR T-cell therapy in the days following administration of the treatment. They saw that the timing of this effect overlapped with patients developing ICANS. Neurological symptoms of hypophosphatemia and ICANS are similar, Nowicki explained.
In the published study, Nowicki and colleagues explored the relationship between hypophosphatemia and ICANS incidence, as well as the biological mechanism that is believed to drive the low phosphate levels.
The researchers grew lymphoma cells in a culture in the laboratory along with the CAR T-cells that are genetically engineered to attack the lymphoma cells. They found that the impact of the CAR T cells on the lymphoma cells was associated with reduced phosphate concentrations in the medium used to grow the cells. Furthermore, CAR T cells co-cultured with lymphoma cells consumed significantly more phosphate than with those that were cultured alone.
The increased phosphate consumption of CAR T cells correlated with their activation after detecting the cancer cells and with increased metabolic activity that needs phosphate to occur. These findings indicate that activity of the CAR T cells results in heightened metabolic demand that could drive hypophosphatemia in patients.
To test this hypothesis, the authors conducted a retrospective analysis of a clinical cohort of 77 patients with B-cell malignancies treated at the University of California, Los Angeles, with CAR T-cell therapy targeted to cancer cells that have a marker called CD-19.
In this cohort, 30 percent of the patients developed ICANS, and approximately 60 percent had hypophosphatemia (defined as serum phosphate concentrations lower than 2mg/dL). Although the serum levels of potassium and magnesium were also low in 52 percent and 72 percent of the patients, respectively, only low phosphate was significantly associated with ICANS, with most patients who developed ICANS (91 percent) also displaying hypophosphatemia. In addition, the patients had lowest phosphate concentrations five days post-CAR T cell infusion, which coincided with the median time to onset of ICANS.
“While some patients who experienced hypophosphatemia did not develop ICANS, we found that the patients with ICANS consistently had more severe degrees of hypophosphatemia,” said Nowicki. “Furthermore, among patients with low phosphate levels, the severity of hypophosphatemia correlated with the severity of the ICANS that they developed.”
The scientists did not observe a significant difference in ICANS severity between patients who had hypophosphatemia and those who did not. However, patients with low phosphate levels experienced significantly longer duration of ICANS than patients with phosphate levels within normal range.
“With larger sample sizes or meta-analyses from other studies in the future, we may be able to detect changes in severity more sensitively,” Nowicki added.
These findings could have implications for monitoring for the development of ICANS in patients receiving CAR T-cell therapies for cancer.
“Clinicians could potentially utilize serum phosphate measurements, which are regularly tested in patients receiving CAR T-cell products, to help predict when they are at greater risk for developing ICANS,” said Nowicki.