STING-activating cyclic dinucleotide-manganese nanoparticles evoke robust immunity against acute myeloid leukemia

• DOI: 10.1016/j.jconrel.2024.03.022
• Publication Date: 2024-03-20T18:44:57Z
• Authors: Marisa E. Aikins; Xiaoqi Sun; Hannah Dobson; Xingwu Zhou; Yao Xu; Yu Leo Lei; James J. Moon
• Keywords: Adult; Myeloid; Manganese; Leukemia; Medical Sciences; Bioinformatics; T-Lymphocytes; Immunity; 610; Antineoplastic Agents; Acute; Biomedical Informatics; Mice; Oncology; Neoplasms; Medical Specialties; Medicine and Health Sciences; Animals; Humans; Nanoparticles; Innate; Immunotherapy

Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults with a 5-year survival rate of 30.5%. These poor patient outcomes are attributed to tumor relapse, stemming from ineffective innate immune activation, T cell tolerance, and a lack of immunological memory. Thus, new strategies are needed to activate innate and effector immune cells and evoke long-term immunity against AML. One approach to address these issues is through Stimulator of Interferon Genes (STING) pathway activation, which produces Type I Interferons (Type I IFN) critical for innate and adaptive immune activation. Here, we report that systemic immunotherapy with a lipid-based nanoparticle platform (CMP) carrying Mn2+ and STING agonist c-di-AMP (CDA) exhibited robust anti-tumor efficacy in a mouse model of disseminated AML. Moreover, CMP immunotherapy combined with immune checkpoint blockade against cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) elicited robust innate and adaptive immune activation with enhanced cytotoxic potential against AML, leading to extended animal survival after re-challenge with AML. Overall, this CMP combination immunotherapy may be a promising approach against AML and other disseminated cancer.