B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in pediatric patients and children of Hispanic ancestry experience higher incidence and mortality rates than others. While cure rates approach 90%, approximately 10% to 20% of patients still relapse. Genomic profiling has identified Ph-like B-ALL as the subtype at highest risk for relapse. Half of all Ph-like B-ALL overexpress the CRLF2 surface protein (CRLF2+ B-ALL). CRLF2 homodimerizes with the IL-7 receptor alpha (IL-7Ra) to comprise a receptor complex that is activated by the cytokine, Thymic Stromal Lymphopoietin (TSLP). TSLP activates the JAK/STAT and PI3/AKT/mTOR pathways which are known to promote cell survival and proliferation. In vitro studies of CRLF2 B-ALL in our laboratory showed that physiological levels (20 pg/ml) of TSLP could activate the TSLP receptor (indicated by STAT5 and ribosomal protein S6 phosphorylation) when stimulated over time. In contrast, we found that supra-physiological levels of TSLP (1 ng/ml or less) induced an initial activation event, but this was followed by a complete shutdown of CRLF2 downstream signaling events that was maintained in the presence of high TSLP. This signal shutdown was correlated with the loss of surface IL-7Ra. The work presented here evaluates the impact of high dose TSLP vs. physiological levels of TSLP on CRLF2 B-ALL in vivo. We make use of novel PDX/xenograft models that expresses human TSLP (hTSLP, mouse TSLP does not activate human CRFL2) created in our lab. Using in vivo bioluminescence analysis of xenografts produced from the MUTZ5 CRLF2 B-ALL cell line, we found that high dose hTSLP induced an 82% decrease in tumor burden (p < 0.0001) as compared to controls with physiological levels of hTSLP. Ongoing studies are evaluating the effect of high dose TSLP on leukemia burden and prolonged survival in a PDX model produced from a Hispanic pediatric patient with CRLF2 B-ALL. Results from these studies will be presented. Taken together, these data suggest that TSLP has promise as a biologic for the treatment of CRLF2 B-ALL.
This work was supported by NIH NCI award R01 CA209829 (KJP & SD).
Citation Format: Caleb Ruiz-Jimenez, Jacqueline Coats, Cornelia Stoian, Ineavely Baez, Hossam Alkashgari, Andy Paz-Aldana, Hannah Choi, Roland Williams, Shadi Farzin Gohar, Sinisa Dovat, Kimberly Payne. High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 470.