AML-190: Anti-TIM-3 Antibody MBG453 in Combination with Hypomethylating Agents (HMAs) in Patients with High-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia: A Phase 1 Study

TIM-3 in Leukemia; Immune Response and Beyond

“…No treatment-related grade 4 IRAEs or deaths had been reported for either combination. Overall, MBG453 plus Dec or Aza is safe and well tolerated in HR-MDS and AML, which showed encouraging response rates and emerging durability as well ( 88 , 90 ). However, whether TIM-3 inhibitors together with HMA treatment could improve clinical outcome requires more evidence from these trials.…”

“…No treatment-related grade 4 IRAEs or deaths had been reported for either combination. Overall, MBG453 plus Dec or Aza is safe and well tolerated in HR-MDS and AML, which showed encouraging response rates and emerging durability as well (88,90) studies included the application of MBG453 in MRD-positive patients after allo-HSCT (NCT04623216) and in combination with a PD-1 inhibitor (NCT0306664), TP53-MDM2 inhibitor (NCT03940352), or Bcl-2 inhibitors plus HMAs (NCT04812548, NCT04150029) for efficacy and safety in MDS and AML. Similarly, a phase I clinical study of the efficacy and safety of another TIM-3 inhibitor, SHR-1702, for the treatment of R/R-AML and HR-MDS is ongoing as well (42 cases; NCT04443751) (86).…”

“…Most phase I/II trials of TIM-3 inhibitors for AML or MDS have been initiated in the past two years, and the trials are still ongoing; thus, the final results have yet to be released. Currently, positive results from several trials have indicated that the ORR of 69 patients with HR-MDS or AML who received MBG453 plus decitabine (Dec) (cutoff 27 Nov 2019, median exposure duration: 8.6 months) or that of 29 patients with HR-MDS or AML who received MBG453 plus azacitidine (Aza) (cutoff 14 Jan 2020, median exposure duration: 3.0 months) was 58% and 70% for HR-MDS, respectively, and 41% and 27%, respectively, for newly diagnosed (ND)-AML (NCT03066648) ( 88 ). Moreover, the ORR was only 24% for MBG453 plus Dec in patients with R/R AML ( Supplementary Table 1 ).…”

Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease

“…Sabatolimab (MBG453) is novel ICIs first-in-class investigational immuno-myeloid therapy that binds to TIM-3 [88,89] (T cell immunoglobulin and mucin domain 3), a novel target expressed on macrophages, monocytes, NK cells, dendritic cells, and T cells. It is involved in regulating innate and adaptive immune responses [90,91] and seems to be expressed on leukemic stem cells (LSCs) and blasts but not on hematopoietic stem cells (HSCs) [92,93] making it a promising target in MDS/AML [88,89,91,[93][94][95][96]. In addition, it may inhibit TIM-3/galectin-9-driven LSC self-renewal via blockade of TIM-3 on LSCs [88,89,[91][92][93][94][95][96].…”

Resistance to Hypomethylating Agents in Myelodysplastic Syndrome and Acute Myeloid Leukemia From Clinical Data and Molecular Mechanism

“…Therefore, targeting LSCs may potentially improve HMA efficiency and prevent disease relapse. The LSC targets CD44, CD47, CD33, CD96, TIM-3, and CD123 antibodies are undergoing investigation ( 113 , 114 ); in particular, TIM-3 antibody, MBG-453, which targets LSCs and leukemia blast cells, is used to combinate with HMA, and has shown encouraging response and durability ( 115 ). This will facilitate its clinical application and further research on LSC target therapies.…”