Abstract 1313: Targeting micelles eradicate acute myeloid leukemia stem cells in a patient-derived leukemia xenograft model

Patients with acute myeloid leukemia (AML) have a very poor prognosis related to a high rate of recurrence rate drug-related toxicity. The current standard “7+3” regimen, with cytarabine and an anthracycline such as daunorubicin (DNR), can achieve complete remission in up to 70-80% of patients, but the majority of patients ultimately suffer from relapse and as many as 30% of patients die from drug-related toxicity during induction therapy. The ability of leukemia stem cells (LSC) to survive chemotherapy is primarily responsible for relapse, and eliminating LSC is ultimately essential for cure. The goal of this project is to develop novel LSC-targeting nanometer-scale micelles, called disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of DNR into both leukemia and leukemia stem cells and eradicate AML from the very root. In this project, we successfully synthesized DC-CTM-DNR. The nanoparticles were 17+/- 6 nm in size and had a payload of 2mg/ml DNR with 100% loading efficiency. DC-CTM were very stable, while an intracellular reductive agent, Glutathione, could reduce the disulfide bonds resulting in micelle dissociation after uptake. Furthermore, using an AML patient-derived xenograft (PDX) model, we showed that 1 mg/kg DC-CTM-DNR-treated mice had significantly less leukemia burden in the bone marrow at week 2 and 4 than both DNR- and PBS-treated mice. Although all mice developed end-stage leukemia by week 8, the DC-CTM-DNR-treated group had significantly smaller leukemia-infiltrated spleens than the PBS group. We further evaluated the effect of treatment on LSC in vivo by secondary transplantation of total bone marrow cells from DNR- and DC-CTM-DNR-treated AML PDX bearing mice into naive NSG mice. At 8 weeks post secondary transplantation, 100% (7/7) and 37.5% (3/8) of mice developed leukemia in the bone marrow from the 1 mg/kg DNR- and DC-CTM-DNR-treated groups, respectively. Spleens from secondary transplant mice in the DC-CTM-DNR group were significantly smaller than the DNR group indicating less leukemia infiltration. Collectively, DC-CTM-DNR exhibited superior anti-leukemia efficacy and could eradicate LSC more effectively than free DNR. Lastly, pharmacokinetic studies were performed with free DNR and DC-CTM-DNR in rats. Consistent with previous results, DC-CTM-DNR had a longer T1/2a, T1/2b, and accumulated under curve area, than free DNR. Toxicology studies also confirmed that DC-CTM-DNR exhibited a superior toxicity profile, with significantly less cardiotoxicity. In conclusion, we have developed a novel LSC-targeting micelle delivery system that can effectively target AML LSC and bulk leukemia cells with decreased systemic toxicity. Ultimately, DC-CTM-DNR has the potential to significantly enhance the complete remission rate and disease-free survival time and decrease the relapse rate and treatment-related mortality for patients with AML. Citation Format: Tzu-Yin Lin, Yuanpei Li, Yanjun Zhu, Hongyong Zhang, Rick Harse, Kit Lam, Brian Jonas, Chong-xian Pan. Targeting micelles eradicate acute myeloid leukemia stem cells in a patient-derived leukemia xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1313.