Background: The overall survival for pediatric/young adult acute myeloid leukemia (AML) approaches 70% with current therapies. In contrast, the outcome for those with the CBFA2T3::GLIS2 (CBF/GLIS) fusion is quite poor. This fusion occurs exclusively in infants and young children < 5 years of age, is the genomic counterpart to the RAM immunophenotype, and is enriched in acute megakaryoblastic morphology. The CBF/GLIS fusion results in a highly aggressive and refractory leukemia with poor response to intensive therapies, including hematopoietic cell transplantation (HCT) with dismal outcomes with an event-free survival of <10%. We previously described a unique transcriptome profile for the CBF/GLIS fusion and discovered and validated expression of folate receptor alpha (FOLR1) on the leukemic cell surface. In addition, we demonstrated lack of expression of FOLR1 in normal hematopoiesis as well as causal link between CBF/GLIS fusion and FOLR1 expression in CBF/GLIS fusion-engineered cord blood stem cells, thus validating FOLR1 as an AML-specific antigen and an ideal candidate for immunotherapeutic targeting. The FOLR1-directed antibody sequence from amatuximab was reformatted in a second-generation lentiviral construct (IgG4 hinge, CD28 transmembrane, 41-BB costimulatory, and CD3ζ stimulatory domains) and generated CARTs (FH-FOLR1 CAR T) were evaluated in CBF/GLIS preclinical models. FH-FOLR1 CAR T demonstrated high target-specific efficacy in pre-clinical models and advanced into a phase I clinical trial for treatment of infants and young children with relapsed/refractory (R/R) CBF/GLIS AML at Seattle Children's Hospital (NCT06609928). A second similar trial is pending at Bambino Gesu Pediatric Hospital; Rome, Italy.

Study Design and Methods: This phase 1, open-label, non-randomized study enrolls children (≥7 kg and ≤ 6 years of age) with R/R FOLR1+ AML, with and without prior history of allogeneic HCT, to examine the safety and feasibility of administering an autologous T-cell product that has been genetically modified to express FOLR1 CAR. Subjects receive a single dose of FH-FOLR1 CAR T. Following apheresis, CD4+ and CD8+ T cells are stimulated with a soluble anti-CD3/28 activation reagent and undergo static transduction with a self-inactivating (SIN) lentiviral vector that directs the expression of the FOLR1 CAR. Modified cells are propagated over 5 days in culture media supplemented with recombinant human cytokines. The product is formulated and cryopreserved, and release testing performed. Once the patient has recovered from any acute toxicities from bridging therapy, lymphodepletion (fludarabine/cyclophosphamide) is administered, followed by infusion of the FH-FOLR1 CAR T on day 0. Bone marrow (BM) evaluation is performed on Day 28. Correlative biology studies evaluate the engraftment and persistence of FH-FOLR1 CAR T in peripheral blood (PB), BM and cerebrospinal fluid (CSF) and to describe anti-leukemic activity (MRD-based response) in the leukemia subjects. This phase 1 study is based on a Bayesian optimal interval design (BOIN) currently with 5 possible dose levels to explore. Additionally, a biologically effective dose (BED) may be determined prior to the maximum tolerated dose (MTD) based on efficacy and persistence of FH-FOLR1 CAR T. Cohort advancement will take place after all patients of the current cohort have been evaluated for dose limiting toxicities. The primary objectives include assessing the safety and toxicity, as well as the feasibility of manufacturing the FH-FOLR1 CAR T in children with R/R AML. Secondary objectives include determination of the engraftment and expansion of the FH-FOLR1 CAR T in BM, PB and CSF, the persistence in PB, and to determine the preliminary anti-leukemia activity of the CAR T in children with FOLR1+ AML.

Trial Status: Enrollment is ongoing at 0.3x106 cells/kg.

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2025
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