Developing a novel biologic for the treatment of high-risk B cell acute lymphoblastic leukemia

Abstract

The subtype of B cell acute lymphoblastic leukemia (B-ALL) at highest risk for relapse overexpresses surface CRLF2 (CRLF2 B-ALL) and disproportionately affects Hispanic children and adults. CRLF2 partners with the IL-7Ra to form a receptor complex 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. Our in vitro studies of CRLF2 B-ALL cells showed that supra-physiological levels of TSLP (1 ng/ml) induced a complete shutdown of TSLP receptor signaling, following the initial activation event. This effect was dose dependent and did not occur at physiological levels (20 pg/ml) of TSLP. This signal shutdown was correlated with the loss of surface IL-7Ra. Using a novel patient-derived xenograft (PDX) model that expresses human TSLP (hTSLP, mouse TSLP does not activate the human TSLP receptor) created in our lab, we showed that high dose hTSLP virtually eliminated human CRLF2 B-ALL cells in vivo. The goal of work presented here was to test whether treatment of CRLF2 B-ALL PDX with high doses of recombinant hTSLP (rhTSLP) could re-capitulate anti-tumor effects of hTSLP observed in our engineered mice and to evaluate its effects on prolonged survival. After 24 days of treatment, rhTSLP reduced the leukemia cell burden by 90% in treated PDX as compared to control PDX that received physiological levels of rhTSLP. Similarly, survival was prolonged in PDX mice receiving high-dose rhTSLP as compared to controls: all 11 control mice died before any of the 11 treated mice died. Taken together, these data suggest that TSLP has promise as a biologic for the treatment of CRLF2 B-ALL.