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Publications

Journal Article Ppublish

PubMed: 39681640 DOI: 10.1038/s41375-024-02493-3

Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia.

Leukemia 39(3):555-567

Authors: Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R Rabin, Terry J Fry, Sarah K Tasian

Affiliations

  • Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
  • Division of Hematology/Oncology/Bone Marrow Transplant and Center for Cancer and Blood Disorders, Children's Hospital of Colorado, Aurora, CO, USA.
  • Texas Children's Hospital Cancer Center and Division of Pediatric Hematology/Oncology, Houston, TX, USA.
  • Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • University of Colorado Anschutz Medical Campus and Gates Institute, Aurora, CO, USA.
  • Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
  • Abramson Cancer Center, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
  • Prinses Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Abstract

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.

MeSH

Cytokines, Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Down Syndrome, Leukemia, Immunotherapy, Therapeutics, Receptors, Antigen, T-Cell

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