Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM‐3 antibody, in combination with decitabine or azacitidine in high‐ or very high‐risk myelodysplastic syndromes

Abstract

Patients with higher-risk myelodysplastic syndromes/neoplasms (MDS) and chronic myelomonocytic leukemia (CMML) have poor prognoses and need novel therapies that produce durable responses with sustained clinical benefit. [1][2][3][4] Initial therapy for higher-risk MDS usually includes a hypomethylating agent (HMA), either azacitidine or decitabine, 5 but benefits are modest, with <20% of patients achieving complete remission (CR) and a median duration of any response <15 months. 6,7 Patients with CMML treated with HMAs 8 also have poor outcomes. 9 T-cell immunoglobulin domain and mucin domain-3 (TIM-3) 10 are expressed on immune cells and myeloid leukemic cells, and function as an inhibitory surface receptor regulating innate and adaptive immune responses, as well as promoting leukemic stem cell (LSC) self-renewal through interaction with galectin-9. [11][12][13][14][15] Increased TIM-3 expression on leukemic progenitors has been described at the time of leukemic progression, suggesting the TIM-3 pathway may be involved in disease transformation to acute myeloid leukemia (AML). 16,17 Conditional knockout of TIM-3 on dendritic cells (DCs) promotes strong antitumor immunity. 18 Sabatolimab, a novel monoclonal antibody targeting TIM-3, may interact with the dysregulated immune microenvironment in MDS, and directly with TIM-3-expressing leukemic progenitors. 11,19,20 Early studies indicate the pharmacokinetic and safety profile of sabatolimab monotherapy is favorable for combination with standard of care therapies in the management of patients with myeloid malignancies. [21][22][23] This Phase Ib trial of sabatolimab + HMA was conducted to evaluate safety, response rate by revised International Working Group (IWG) criteria, and durability of response in patients with high-or very high-risk MDS (HR/vHR-MDS) or CMML. 24