Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that accounts for 10-15% of pediatric and 25% of adult ALL cases. Approximately 20-25% of pediatric and 50% of adult patients with T-ALL relapse following induction therapy, and the prognosis after relapse is dismal, with 3-year event-free survival of only 10-15%. Thus, there is a clear unmet clinical need for better therapies for T-ALL. CXCL12 (stromal-derived factor-1, SDF1) is a CXC chemokine that is constitutively expressed at high levels in the bone marrow. CXCR4 is the major receptor for CXCL12 and is by far the most highly expressed chemokine receptor on T-ALL cells. Two groups recently showed that genetic loss of CXCR4 signaling in murine or human T-ALL cells markedly suppressed their growth in vivo. Here we explore the hypothesis that inhibition of the CXCR4 signaling with a potent new CXCR4 antagonist, BL-8040 alone, or in combination with ABT263 (navitoclax), a BCL2/BCLXL antagonist, will have therapeutic activity against T-ALL.
To test this hypothesis, we xenotransplanted a human T-ALL cell line (P12/Ichikawa cells) or 5 different patient-derived T-ALL xenografts into non-irradiated NSG mice. In each case, the T-ALL cells were allowed to engraft and then mice were randomly assigned to one of four treatment groups: 1) vehicle control; 2) BL-8040 alone; 3) ABT263 alone; 4) combined BL-8040 and ABT263. Treatment was given for 2 weeks, and leukemia burden monitored weekly by bioluminescent imaging or by flow cytometry to quantify human CD45+ T-ALL cells in the blood. A minimum of 10 mice in each cohort from two independent experiments were analyzed (Figure 1). A significant reduction in T-ALL burden was observed in all T ALL samples after treatment with BL8040 alone, with a mean fold-decrease compared with control mice after 2 weeks of treatment of 966 ± 651 (range 16-3,486). Consistent with a prior report, the response to ABT263 alone was more variable, with responses seen in 4 of 6 T-ALL samples. All T-ALL samples had a marked response to the combination of BL-8040 and ABT263, with a mean fold decrease of 4,389 ± 2,602 (range, 139-15,199). A previous study suggested that inhibition of CXCR4 signaling may suppress Myc expression (Pitt et al, Cancer Cell, 2015), which is relevant, since overexpression of Myc secondary to mutations in the Notch pathway are common in T-ALL. However, we observed no difference in Myc protein expression or expression of Myc target genes following BL-8040 treatment. Consistent with this observation, treatment with BL8040 had no impact on the cell cycle status of T-ALL cells in vivo. Of note, we observed a marked decrease in Akt and Erk phosphorylation following BL8040, suggesting that CXCR4 signaling may regulate T ALL survival in vivo by suppressing these pathways.
Conclusion. Collectively, these data suggest that BL-8040, either alone or in combination with ABT263, is highly active in T-ALL and support our ongoing clinical trial of BL-8040 in combination with nelarabine for patients with relapsed T-ALL (NCT02763384).
Figure 1. Figure 1.
Disclosures
Uy: GlycoMimetics: Consultancy; Curis: Consultancy. Vainstein:Biolinerx: Employment. Sorani:BioLineRx Ltd.,: Employment. Bohana-Kashtan:BioLineRx Ltd.,: Employment, Equity Ownership; Cell Cure Neurosciences: Equity Ownership. Shaw:BioLineRx Ltd.: Employment, Equity Ownership.
Constitutive Notch pathway activation in murine ZMYM2-FGFR1–induced T-cell lymphomas associated with atypical myeloproliferative disease