Session: 702. CAR-T Cell Therapies: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Diseases, Lymphoid Malignancies, Study Population, Animal model
Methods: In the current studies, we tested the hypothesis that co-targeting extracellular TSLPR with CART immunotherapy and intracellular JAK/STAT signaling with ruxolitinib would induce synergistic anti-leukemia activity in CRLF2-rearranged (CRLF2-R) Ph-like and DS-ALL using cell lines and patient-derived xenograft (PDX) models.
Results: TSLPRCART monotherapy showed effective and durable inhibition of leukemia proliferation in vitro in CRLF2-R Ph-like ALL cell lines and in vivo in both CRLF2-R Ph-like ALL (n=4) and DS-ALL (n=3) PDX models. However, we unexpectedly observed fatal TSLPRCART-induced toxicity in ALL PDX mice treated at higher CART doses that correlated with high levels of in vivo inflammatory cytokine production. Interestingly, simultaneous TSLPRCART and ruxolitinib co-administration prevented early animal death, but also significantly reduced T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse. Importantly, delaying ruxolitinib co-exposure by two weeks completely preserved desired anti-leukemia TSLPRCART activity and prevented cytokine release syndrome (CRS)-type mortality, resulting in long-term ‘cure’ and survival of Ph-like ALL PDX mice. We further observed in additional Ph-like ALL PDX model experiments that ruxolitinib withdrawal following TSLPRCART-induced leukemia remission resulted in recovery of CAR T cell functionality with in vivo re-expansion of TSLPRCART, IFN-γ production, and leukemia clearance after subsequent CRLF2/TSLPR+ ALL ‘relapse’ rechallenge. These results were fully recapitulated in DS-ALL PDX models, validating JAK/STAT pathway hyperactivation and the TSLPR antigen as a critical immunotherapeutic target, and with CD19CART in orthogonal in vitro ALL cell line and in vivo PDX model studies.
Conclusion: Ruxolitinib-induced inhibition of TSLPRCART and CD19CART fitness and anti-ALL activity is robust, but reversible. Biologically-appropriate time sequencing of CART immunotherapy and ruxolitinib achieved both effective acute CRS mitigation and robust long-term anti-ALL activity in preclinical models, which has high translational potential as a relapse prevention ‘maintenance’ strategy for patients with CRLF2-R Ph-like ALL or DS-ALL.
Disclosures: Bagashev: Carisma Therapeutics: Current Employment. Ross: Parexel International: Current Employment. Fry: Sana Biotechnology: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; United States Patent and Trademark Office: Patents & Royalties: WO2019178382A1; United States Patent and Trademark Office: Patents & Royalties: WO2017205747A1; United States Patent and Trademark Office: Patents & Royalties: WO2015084513A1. Tasian: Amgen: Other: Travel support; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Incyte Corporation: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Wugen, Inc: Membership on an entity's Board of Directors or advisory committees.
See more of: Oral and Poster Abstracts