Exogenous Antigen Upregulation Empowers Antibody Targeted Nanochemotherapy of Leukemia

Abstract

Acute myeloid leukemia (AML) is afflicted by a high‐mortality rate and few treatment options. The lack of specific surface antigens severely hampers the development of targeted therapeutics and cell therapy. Here, it is shown that exogenous all‐trans retinoic acid (ATRA) mediates selective and transient CD38 upregulation on leukemia cells by up to 20‐fold, which enables high‐efficiency targeted nanochemotherapy of leukemia with daratumumab antibody‐directed polymersomal vincristine sulfate (DPV). Strikingly, treatment of two CD38‐low expressing AML orthotopic models with ATRA and DPV portfolio strategies effectively eliminates circulating leukemia cells and leukemia invasion into bone marrow and organs, leading to exceptional survival benefits with 20–40% of mice becoming leukemia‐free. The combination of exogenous CD38 upregulation and antibody‐directed nanotherapeutics provides a unique and powerful targeted therapy for leukemia.

CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia

“…Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous myeloid cancer diagnosed mainly in elderly people and is associated with poor prognosis. − Cytarabine and daunorubicin-based standard chemotherapy, though improving the survival of eligible younger patients, is perplexing with high systemic toxicity, making most elderly patients ineligible, with a 5 year survival rate below 10%. − With an improved understanding of AML genomics, several important molecular targets influencing prognosis and treatment decisions have been identified. − Mutations in FMS-like tyrosine kinase 3 (FLT3), including FLT3 internal tandem duplications (FLT3-ITD) and the FLT3 tyrosine kinase domain (FLT3-TKD), are most frequently detected in AML patients (∼30%) and are correlated with an inferior prognosis compared to wild-type FLT3 AML. − Recent approval of FLT3 inhibitors, such as midostaurin, sorafenib (SOR) and gilteritinib, has altered the treatment landscape for FLT3 mutant AML patients. , However, due to the emergence of drug resistance, FLT3 inhibitors generally have limited monotherapy efficacy and are often administered in combination with chemotherapeutics or other small molecular targeted drugs, such as B-cell lymphoma-2 (BCL-2) inhibitors …”