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Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia
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Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia
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Journal Article
Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia
2025
Overview
CRLF2
rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) and induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss. We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against
CRLF2
-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in
CRLF2-
rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse, which was abrogated by time-sequenced/delayed ruxolitinib co-exposure. Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia ‘maintenance’ relapse prevention for
CRLF2
-rearranged Ph-like and DS-ALL.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 59/5
/ 64
/ 64/60
/ 96
/ 96/95
/ Acute lymphoblastic leukemia
/ Animals
/ Antigens
/ Down Syndrome - complications
/ Humans
/ Kinases
/ Leukemia
/ Medicine
/ Mice
/ Nitriles
/ Oncology
/ Patients
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy
/ Receptors, Cytokine - antagonists & inhibitors
/ Receptors, Cytokine - genetics
/ Thymic stromal lymphopoietin
/ Thymus
/ Toxicity
