Diamanti, Paraskevi;
Bailey, Bethan K;
Iheanacho, Obinna E;
Moppett, John P;
Nathwani, Amit C;
Blair, Allison;
(2025)
Expression and treatment of ROR1+ cells with bispecific T-cell engagers in pediatric acute lymphoblastic leukemia.
Blood Advances
, 9
(13)
pp. 3190-3201.
10.1182/bloodadvances.2024013814.
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Abstract
Receptor tyrosine kinase-like orphan receptor (ROR)1 is overexpressed in some hematological cancers but has low expression in normal tissues, making it a potential therapeutic target. We investigated this therapeutic potential in childhood B-cell precursor (BCP) and T-cell acute lymphoblastic leukemia (T-ALL) cases. The proportion of ROR1<sup>+</sup> cells was significantly higher in T-ALL (median, 13.8%; range, 2.9%-87%) than BCP-ALL (6%, 0.3%-83%, P = .02). Antigen density was also lower in BCP-ALL (median, 1027; range, 876-2588) compared to T-ALL (1089, 865-1527). In leukemia propagating cells (LPCs), ROR1 levels were highest in CD34<sup>-</sup>/CD19<sup>+</sup> and CD34<sup>-</sup>/CD7<sup>+</sup> subpopulations. Notably, ROR1<sup>+</sup> LPC, in both BCP-ALL and T-ALL, survived induction therapy and their numbers increased post treatment. Subsequently, ROR1 bispecific T-cell engagers (T<inf>eng</inf>) were tested on primary cases in vitro and in vivo. Addition of ROR1 T<inf>eng</inf> in vitro reduced ALL survival to 44% in BCP-ALL and 58% in T-ALL, compared to T cells alone (94% and 84%, respectively; P ≤ .01). When NOD.Cg-Prkdc<sup>scid</sup>Il2rγ<sup>tm1Wjl</sup>/SzJ mice engrafted with primary leukemia were treated with ROR1 T<inf>eng</inf>, disease burden was reduced by up to 520-fold (from 15.6% to 0.03%) in ROR1<sup>+</sup> cells and 68-fold (58% to 0.9%) in CD19<sup>+</sup> cells in BCP-ALL. In T-ALL cases, there was a fourfold reduction (from 1.2% to 0.3%) in ROR1<sup>+</sup> and 2.3-fold (from 83.7% to 36.7%) in CD7<sup>+</sup> levels. This resistance of ROR1<sup>+</sup> cells to current therapies makes it an important target. Moreover, as ROR1 T<inf>eng</inf> were at least comparable to CD19 T<inf>eng</inf> in vivo, they could be considered for the treatment of refractory BCP-ALL.
| Type: | Article |
|---|---|
| Title: | Expression and treatment of ROR1+ cells with bispecific T-cell engagers in pediatric acute lymphoblastic leukemia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/bloodadvances.2024013814 |
| Publisher version: | https://doi.org/10.1182/bloodadvances.2024013814 |
| Language: | English |
| Additional information: | © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Hematology, FREE SURVIVAL, YOUNG-ADULTS, ROR1, BLINATUMOMAB, CHEMOTHERAPY, CHILDREN, POPULATIONS, EFFICACY, THERAPY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213439 |
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