Patients with B-cell malignancies who had hypophosphatemia experienced a higher incidence and severity of neurologic side effects from chimeric antigen receptor (CAR) T-cell therapy, according to a study by Nowicki et al published in Cancer Immunology Research. The study results imply that phosphorous level monitoring could alert physicians to the development of neurologic toxicity associated with CAR T-cell therapy—known as immune effector cell–associated neurotoxicity syndrome (ICANS)—which affects about 50% of CAR T-cell therapy recipients.

Although CD19–targeted CAR T-cell therapy has revolutionized the treatment of relapsed or refractory B-cell lymphomas and leukemias, the therapy is associated with cytokine-release syndrome and ICANS, which can manifest as confusion, delirium, aphasia, impaired motor skills, and somnolence.

In this study, the researchers investigated whether CAR T-cell effector metabolic activity is associated with increased extracellular phosphate consumption and assessed a possible association between hypophosphatemia and ICANS.

Study Methodology

The researchers cocultured lymphoma cells expressing the CD19 antigen with CD19-targeted CAR T cells. To understand the relationship between hypophosphatemia and ICANS incidence, they conducted a retrospective analysis of 77 patients with B-cell malignancies treated with CD19-targeted CAR T-cell therapy (tisagenlecleucel or axicabtagene ciloleucel at the University of California, Los Angeles [UCLA]) between March 2018 and July 2020.

Key Findings

The researchers found that lymphoma cell killing in vitro was associated with reduced phosphate concentrations in the culture media. In addition, CAR T cells cocultured with lymphoma cells consumed significantly more phosphate than when cultured alone. The increased phosphate consumption of CAR T cells correlated with their activation following CD19 antigen recognition (as shown by increased cytokine release) and with elevated phosphate-dependent metabolic activity. According to the researchers, these findings indicate that CAR T cell–modulated cell killing results in a heightened metabolic demand that could drive hypophosphatemia in patients.

In the clinical cohort, 30% of the patients developed ICANS, and approximately 60% had hypophosphatemia (defined as serum phosphate concentrations lower than 2 mg/dL). Although the serum levels of potassium and magnesium were also low in 52% and 72% of the patients, respectively, only low phosphate was significantly associated with ICANS, with most patients who developed ICANS (91%) also displaying hypophosphatemia. In addition, the patients had the lowest phosphate concentrations 5 days post–CAR T-cell infusion, which coincided with the median time to ICANS onset.

Clinical Significance

According to the Theodore S. Nowicki, MD, PhD, Assistant Professor-in-Residence in the Departments of Pediatrics (Hematology/Oncology) and Microbiology, Immunology, & Molecular Genetics at the David Geffen School of Medicine, UCLA, and lead author of the study, the findings could have implications for monitoring the development of ICANS in patients receiving CAR T-cell therapy.

“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 Dr. Nowicki in a statement.

Disclosure: Dr. Nowicki reported honoraria from consulting with Allogene Therapeutics, PACT Pharma, and Adaptive Biotechnologies. Funding for this study was provided by the National Institutes of Health, National Cancer Institute, UCLA Clinical and Translational Science Institute, Jonsson Comprehensive Cancer Center, and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. For full disclosures of the study authors, visit aacrjournals.org/cancerimmunolres.