TIM-3 pathway dysregulation and targeting in cancer

Abstract

Introduction: Dysfunction of the immune system is a hallmark of cancer. Through increased understanding of the complex interactions between immunity and cancer, immunotherapy has emerged as a treatment modality for different types of cancer. Promising activity with immunotherapy has been reported in numerous malignancies, but challenges such as limited response rates and treatment resistance remain. Furthermore, outcomes with this therapeutic approach in hematologic malignancies are even more limited than in solid tumors. T-cell immunoglobulin domain and mucin domain 3 (TIM-3) has emerged as a potential immune checkpoint target in both solid tumors and hematologic malignancies. TIM-3 has been shown to promote immune tolerance, and overexpression of TIM-3 is associated with more aggressive or advanced disease and poor prognosis.Areas covered: This review examines what is currently known regarding the biology of TIM-3 and clinical implications of targeting TIM-3 in cancer. Particular focus is given to myeloid malignancies. Expert opinion: The targeting of TIM-3 is a promising therapeutic approach in cancers, including hematologic cancers such as myeloid malignancies which have not benefited much from current immunotherapeutic treatment approaches. We anticipate that with further clinical evaluation, TIM-3 blockade will emerge as an important treatment strategy in myeloid malignancies.

TIM-3 in Leukemia; Immune Response and Beyond

“…Currently, the TIM-3 inhibitors used in clinical trials include MBG453 (also known as Sabatolimab), TSR-022, BMS-986258, LY3321367, SYM023, BGB-A425, and SHR-1702 ( 86 , 87 ). However, MBG453 and SHR-1702 have begun to be used in clinical trials for leukemia immunotherapy only ( 86 ) ( Table 2 and Figure 2 ).…”

“…Although a number of TIM-3 blockade clinical trials for malignant tumor have been reported, MBG453 is the only inhibitor that has shown preliminary efficacy and safety in clinical studies for MDS and AML ( 86 ). Currently, eight phase I/II clinical trials are ongoing for AML and MDS with MBG453 monotherapy or the combination of different agents such as hypomethylating agents (HMAs), PD-1 inhibitors, HDM201 (an MDM2 inhibitor), and venetoclax.…”

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…In the context of TIM-3 dysregulation which is a distinct AML marker present predominantly on leukemic stem cells (LSCs), TIM3 is absent on normal HSCs [ 150 , 151 , 152 ]. However, its presence on MDS blasts cells is associated with disease progression and leukemic transformation, and this is evident by the upregulation of pro-proliferative or anti-apoptotic genes [ 151 ].…”

“…Galectin 9 (Gal-9), one of the ligands of TIM-3 receptor is found excessively expressed on myeloid-derived suppressor cells (MDSCs), exerting an inhibitory effect on immune and inflammatory reactions [ 153 ]. The TIM-3/Gal-9 pathway takes part in MDSC-induced T cell exhaustion [ 150 , 151 , 152 , 153 ]. It also activates NF-κB and β-catenin signaling and promotes self-renewal in TIM-3 + LSCs [ 154 ].…”

TIM‐3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways

“…Sabatolimab (MBG453), an anti‐human TIM‐3 humanized IgG4 monoclonal antibody with an S228P mutation, has been tested for the treatment of myeloid malignancies, including AML, high‐risk myelodysplastic syndromes, and chronic myelomonocytic leukemia. The combination therapy of sabatolimab and hypomethylating agents (HMAs) has exhibited preliminary encouraging efficacy and safety findings in clinical trials (NCT03066648 for phase I and NCT03946670 for phase II) 62 . Based on these preceding studies, a phase III multicenter, double‐blind, two‐arm parallel‐group, randomized, placebo‐controlled study of MBG453 added to azacitidine, started in 2020 (NCT04266301).…”