Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia DOI Creative Commons
Tommaso Balestra, Lisa M Niswander, Asen Bagashev

et al.

Leukemia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) 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 children with relapsed/refractory B-ALL, ~50% CD19CART-treated patients relapse again, many CD19 loss. We previously reported preclinical activity thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against -overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART would superior first validated potent TSLPRCART-induced inhibition proliferation vitro CRLF2- rearranged lines vivo DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished proliferation, blunted cytokine production, and/or facilitated relapse, which was abrogated time-sequenced/delayed co-exposure. Importantly, co-administration prevented fatal cytokine-associated toxicity PDX mice. Upon withdrawal, functionality recovered clearance subsequent rechallenge. These translational studies demonstrate effective two-pronged therapeutic strategy mitigates acute CART-induced hyperinflammation provides potential anti-leukemia ‘maintenance’ prevention for -rearranged DS-ALL.

Language: Английский

Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia DOI Creative Commons
Tommaso Balestra, Lisa M Niswander, Asen Bagashev

et al.

Leukemia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) 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 children with relapsed/refractory B-ALL, ~50% CD19CART-treated patients relapse again, many CD19 loss. We previously reported preclinical activity thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against -overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART would superior first validated potent TSLPRCART-induced inhibition proliferation vitro CRLF2- rearranged lines vivo DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished proliferation, blunted cytokine production, and/or facilitated relapse, which was abrogated time-sequenced/delayed co-exposure. Importantly, co-administration prevented fatal cytokine-associated toxicity PDX mice. Upon withdrawal, functionality recovered clearance subsequent rechallenge. These translational studies demonstrate effective two-pronged therapeutic strategy mitigates acute CART-induced hyperinflammation provides potential anti-leukemia ‘maintenance’ prevention for -rearranged DS-ALL.

Language: Английский

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