Abstract 486: Enhanced survival of lethally-irradiated mice with HSC reconstitution in combination with the E-selectin antagonist, GMI-1271 (uproleselan)

Abstract

Abstract The involvement of the adhesion molecule E-selectin and its interactions with E-selectin ligands as pertains to hematopoietic stem cells (HSC) and transplantation has been investigated (Winkler et al. 2012; Winkler et al. 2014). These preclinical studies focused on the role of E-selectin and the use of uproleselan, an E-selectin antagonist, during HSC mobilization in harvesting procedures of donors to accelerate recovery in transplant recipients. However, the impact of E-selectin and uproleselan administration on transplant recipients was less clear. In the current investigations we assessed the survival outcome of bone marrow depleted mice when reconstituted with HSC in combination with uproleselan. Lethally-irradiated, bone marrow depleted C57BL/6 mice were reconstituted with bone-marrow harvested from a congenic strain. Twenty-four hours post irradiation (6Gy x2), cohorts of mice (n=10/group) were injected i.v. with 1 × 106 cells (study day 0) from congenic donors using three i.p. dosing regimens with 40 mg/kg uproleselan. These regimens were: (a) bid on study days 0 and1; (b) bid on study days 1 and 2; and (c) bid on study day 1 only. Control groups in this study included irradiated mice alone (expected survival = 0%), non-irradiated mice alone (expected survival = 100%), and irradiated, reconstituted mice (no uproleselan). The survival of mice was determined over the course of the study (Day 0 to 30). Additional parameters of evaluation included sinusoidal obstructive syndrome such as hepatic veno-occlusive disease known to be E-selectin dependent and a complication of HSC transplantation. Treatment with uproleselan as part of the transplant regimen significantly increased the median survival time (MST) of mice compared with the control group – the MST of mice treated with uproleselan and HSC was >30 days with 80-90% of mice alive at study completion. In contrast, the MST of irradiated mice (no transplant) was 11.5 days with no survivors at study conclusion. The MST of mice irradiated and transplanted with congenic HSC was 9 days with 40% survival on day 30. The impact of uproleselan on survival represented a >233.3% increase in life span. Flow cytometric analysis in all surviving mice on day 30 showed that the mean percentage of CD45.1+ cells from donor congenic mice was approximately 90% (blood and bone marrow) indicating that all surviving mice were successfully reconstituted. In summary, we report on a novel therapeutic use of inhibitors of E-selectin, such as uproleselan, which results in the increased survival of mice when combined with HSC transplantation for reconstitution of depleted and compromised bone marrow. The impact on increased host survival could extend to the use of peripheral blood and stem cell transplantations as a therapeutic option in various malignancies where curative intent is intended. Citation Format: William E. Fogler, Dylan Daniel, Sheri Barnes, Alden Wong, David Draper, John L. Magnani. Enhanced survival of lethally-irradiated mice with HSC reconstitution in combination with the E-selectin antagonist, GMI-1271 (uproleselan) [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 486.