Study of an Innovative Therapy Using CAR-T Cells Targeting IL-1RAP in Patients With High-Risk Myelodysplastic Syndromes (MDS

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders whose incidence increases with age, characterized by an oligoclonal involvement of hematopoietic stem cells (HSCs) and dysplasia of myeloid lineages. These abnormalities result in peripheral blood cytopenias, most frequently anemia. Treatment of lower-risk MDS is based on growth factors or repeated transfusions, whereas in higher-risk MDS, therapy relies on allogeneic hematopoietic stem cell transplantation whenever feasible, chemotherapy, or hypomethylating agents. However, prognosis remains poor due to complex cytogenetic and molecular abnormalities and the risk of progression to acute myeloid leukemia (AML). This is particularly the case for myelodysplastic syndromes with excess blasts (MDS-EB), which represent a pre-leukemic condition with rapid evolution toward AML. The standard treatment for MDS-EB consists of hypomethylating agents, with hematopoietic stem cell transplantation considered when possible. Nonetheless, a significant proportion of patients are refractory to these therapies, and few alternatives are available for patients who are ineligible for transplantation due to age and/or comorbidities.

Several research groups are actively seeking new targets to develop additional therapeutic strategies such as immunotherapy, following the success of CAR-T cell approaches. CAR-T cell therapy (Chimeric Antigen Receptor T-cell therapy) is a form of cellular immunotherapy that leverages the patient's own immune system to fight hematologic malignancies. CAR-T cells are genetically engineered T lymphocytes designed to recognize and eliminate cancer cells. The impressive outcomes achieved with CD19- and BCMA-targeted CAR-T cells in lymphoid malignancies (such as diffuse large B-cell lymphoma or multiple myeloma) support the development of such anti-tumor cellular immunotherapies in myeloid diseases, including MDS.

To date, preclinical research has demonstrated proof-of-concept for CAR-T cell therapy in AML, and a limited number of clinical studies are ongoing, mainly early-phase (I/II) trials targeting markers such as CD33, CD123, or NKG2D ligands. However, only a few investigations involve CAR-T cells in MDS, aside from one CD123-targeted CAR-T cell study, which highlights the therapeutic potential of this strategy for the disease.

Interleukin-1 receptor accessory protein (IL-1RAP) has emerged as a promising therapeutic target. IL-1RAP is a cell surface protein that forms a complex with the IL-1 and IL-33 receptors. IL-1 is a pro-inflammatory cytokine that activates NF-κB signaling in response to infection, stress, or tissue damage. In MDS, IL-1RAP expression levels have been shown to correlate with the percentage of bone marrow blasts. Additional studies support IL-1RAP as a viable therapeutic target. Moreover, IL-1RAP overexpression induces oncogenic signaling pathways in AML, contributing to the pathophysiology of these neoplasms. Importantly, IL-1RAP overexpression appears to be restricted to leukemic stem cells and is absent in the healthy stem cell compartment. Its selective expression on leukemic cells therefore makes it an ideal target for CAR-T cell immunotherapy.

This project will require the collection of bone marrow and blood samples from patients with MDS, either newly diagnosed or currently undergoing treatment. A bone marrow sample will be obtained as part of routine clinical care during a diagnostic bone marrow aspiration performed in the context of suspected MDS, during assessment of treatment response to azacitidine with or without venetoclax, or in the case of suspected relapse after these treatments or after allogeneic HSC transplantation. Peripheral blood will be collected at the same time as the bone marrow sample and the routine blood draw for complete blood count required for evaluation of the bone marrow aspirate.

IL-1RAP is thus a potential target for CAR-T cell therapy development. Furthermore, IL-1RAP overexpression may contribute to a pro-inflammatory microenvironment partly responsible for the progression of high-risk MDS to AML.

If we confirm the cytotoxic activity of IL-1RAP-targeted CAR-T cells in vitro and in vivo in our humanized PDX murine model of high-risk MDS, we intend to submit a national clinical research proposal (PHRC-K) to initiate a phase 1 clinical trial in patients with high-risk MDS with excess blasts who are refractory to conventional therapies and ineligible for allogeneic HSC transplantation, or who have relapsed after transplantation.