Le Q, Hadland B, Smith JL, et al. CBFA2T3-GLIS2 Model of Pediatric Acute Megakaryoblastic Leukemia Identifies FOLR1 as a CAR T Cell Target. Journal of Clinical Investigation. 2022; (doi: 10.1172/JCI157101).
Scientists have identified FOLR1, a gene specific to CBFA2T3-GLIS2 (C/G) fusion oncoprotein, as a potential therapeutic target for acute megakaryoblastic leukemia (AML). Fusion oncoproteins are often implicated in pediatric AML, and xenograft models associate the C/G type with generally poor prognoses. The researchers note that expression of the protein stimulates transformation of hematopoietic stem/progenitor cells (CB HSPCs) in human cord blood in a way that invites particularly aggressive cancer, especially in babies and very young children. Chimeric antigen receptor T cells directed at FOLR1 performed well against C/G AML in in vitro and xenograft models, a pre-clinical sign of efficacy. Before the therapy can advance to the clinical phase, potential safety concerns must be addressed. The endothelial niche is important for promoting leukemic transformation of C/G-transduced CB HSPCs, with investigators noting this activity takes place in an endothelial cell co-culture. FOLR1 is also expressed in renal and pulmonary epithelium, which raises concern about toxicity.
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