New treatment strategy for acute myeloid leukemia proposed by Tokai University

A research group led by Assistant Professor Kaito Harada of the Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, Tokai University has identified a novel immune cell therapy strategy for acute myeloid leukemia (AML). By combining CAR-T cells targeting molecules specifically expressed in AML and leukemic stem cells with microRNA supplementation, this approach may overcome the limitations of conventional CAR-T cell therapy. The findings were published in the Journal of Hematology & Oncology.

AML is a blood cancer characterized by the abnormal proliferation of immature myeloid cells, and it carries a high relapse rate with many cases still having a poor prognosis. In recent years, CAR-T cell therapy has shown remarkable efficacy in treating certain blood cancers. However, establishing a safe and effective treatment for AML remains challenging due to shared antigen expression between cancer cells and normal hematopoietic stem cells, as well as immune suppression driven by the tumor microenvironment.

The research group had previously focused on IL1RAP (interleukin-1 receptor accessory protein), a surface molecule that is highly expressed on AML cells and leukemic stem cells but is largely absent on normal hematopoietic stem cells and had been developing highly AML-specific CAR-T cells.

In this study, the group developed CAR-T cells targeting IL1RAP and evaluated their efficacy and safety. The results confirmed suppression of leukemic cell proliferation and prolonged survival in both in vitro experiments and patient-derived xenograft (PDX) mouse models engrafted with patient-derived AML cells. The effect on normal hematopoietic stem cells was limited, indicating that IL1RAP is a promising therapeutic target for AML.

Detailed analysis also revealed that interaction with AML cells reduces microRNA-142 levels within T cells, leading to impaired energy metabolism and functional exhaustion. CAR-T cell exhaustion is recognized as a major factor behind reduced treatment efficacy and diminished persistence.

The group then investigated a method of supplementing CAR-T cells with a synthetic microRNA-142 mimic. The method restored energy metabolic function and antileukemic activity. In patient-derived AML model mice, this resulted in meaningfully greater antitumor effects and significantly prolonged survival compared with CAR-T treatment alone. These results demonstrate that microRNA-142 supplementation is a fundamental molecular strategy capable of simultaneously enhancing both the efficacy and persistence of CAR-T cells.

These findings present a new concept: improving safety by targeting IL1RAP, which is specifically expressed in AML, while using microRNA to counteract the functional decline of CAR-T cells. Since CAR-T cell exhaustion is a challenge shared across cancer immunotherapy as a whole, the microRNA-142-mediated functional recovery strategy demonstrated here suggests potential applicability not only in AML but also in other hematologic malignancies and solid tumors. Further advances in clinical research are expected to expand the range of treatment options available for refractory leukemia.

Going forward, the research group plans to conduct further preclinical evaluation of the safety and efficacy of microRNA-142-supplemented CAR-T cells and to optimize the manufacturing process in preparation for clinical application. The group also intends to explore the potential of extending this molecular regulatory strategy to other CAR-T cells and immune cell therapies.

Journal Information
Publication: Journal of Hematology & Oncology
Title: MicroRNA-142 improves IL1RAP CAR-T cell activity in acute myeloid leukemia
DOI: 10.1186/s13045-025-01755-6