Hypophosphatemia Correction Reduces ICANS Incidence and Duration in CAR T-cell Therapy: A Pooled Clinical Trial Analysis.

A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients. SIGNIFICANCE: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.

IGF2BP3 as a Prognostic Biomarker in Well-Differentiated/Dedifferentiated Liposarcoma.

BACKGROUND: Although IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking. METHODS: We examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation. RESULTS: Within the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034). CONCLUSION: IGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.

Hypophosphatemia Due to Increased Effector Cell Metabolic Activity Is Associated with Neurotoxicity Symptoms in CD19-Targeted CAR T-cell Therapy.

A major complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents as aphasia, confusion, weakness, somnolence, seizures, and coma. This is similar to the neurologic manifestations of hypophosphatemia, which can result from sudden increases in metabolic demand for phosphorylated intermediates (e.g., refeeding syndrome and sepsis). Given these similarities, we investigated whether CAR T-cell effector metabolic activity is associated with increased extracellular phosphate consumption and a possible association between hypophosphatemia and ICANS. In vitro 4-1BB and CD28 CD19-targeted CAR T-cell effector activity was found to be associated with increased consumption of media phosphorus, which was temporally associated with increased single-cell effector secretomic activity and increased phosphorus-dependent metabolic demand of the CAR T cells. A clinical cohort of 77 patients treated with CD19-targeted CAR T-cell therapy demonstrated a significant anticorrelation between serum phosphorus and ICANS incidence and severity, with earlier onset of hypophosphatemia after CAR T-cell infusion more likely to result in neurotoxicity. These results imply phosphorous level monitoring could alert to the development of ICANS in clinical scenarios. See related Spotlight by Tobin et al., p. 1422.