Abstract 615: Tim-3 as an immune therapy target, mechanism and action, and prognostic values with its ligands in patient stratification

Abstract

Abstract BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), many cancer patients cannot benefit from these therapies. T cell immunoglobulin and mucin domain 3 (TIM-3) has emerged as one of the next generation ICI targets, with potentially lower toxicity and higher safety compared to CTLA-4 and PD-1 blockades. TIM-3 is widely expressed in different immune lineages playing various roles such as mediating immune tolerance and regulating innate immune response. However, the mechanism of action of TIM-3 inhibition in different malignancies is not completely understood. Whether the expression and genomic status of TIM-3 and its ligands, Ceacam-1, galectin-9, HMGB1 and phosphatidyl serine (PtdSer) are associated with clinical outcome or any indication would be essential for patient selection for TIM-3 targeting therapies. METHODS: Human PD-1/TIM-3 double-knock-in mice (PD-1/TIM-3 dKI HuGEMM™) engrafted with CT26.WT tumor model were used to test human PD-1 antibody (Keytruda) and TIM-3 antibody (MBG453). Immune phenotyping of blood, tumor draining lymph node (TDLN) and spleen tissues were assessed by flow cytometry at different time points after dosing. Cytokine levels in serum were measured by MSD assays at 48 hours post the 3rd dose and at study termination. Patient genomic and clinical data for various cancer types such as colorectal adenocarcinoma and pancreatic adenocarcinoma were collected for prognostic biomarker analysis. RESULTS: In the in vivo efficacy study of single and combination treatment with Keytruda and MBG453, we observed that NK cells were induced by anti-TIM-3 treatment, alone and in combination, in both blood and TDLN. This indicates TIM-3 blockade may lead to NK cell proliferation in the TME to enhance tumor killing. Transcriptomic analysis on thousands of patients from TCGA showed that high expression of TIM-3 was highly associated with MSI-H and MSI/CIMP subtypes of colorectal adenocarcinoma, suggesting the potential of Tim-3 target therapy in combination with PD-1 blockade in colorectal cancers. By survival analysis, we observe that one of the TIM-3 ligands, HMGB1, expression is associated with patient OS and PFS with pancreatic adenocarcinoma, but not in colorectal cancers. Furthermore, TIM-3 expression was associated with many immune cell signatures, including macrophages, dendritic cells, CD8+ memory T cells, CD4+ memory T cells and Tregs in both colorectal and pancreatic adenocarcinoma. CONCLUSIONS: Evaluation in preclinical model demonstrated that TIM-3 blockade may cause NK cell proliferation to enhance anti-tumor immunity. In addition, the expression and genomic alteration of TIM-3 and its ligand have prognostic values for certain cancers. Citation Format: Jia Xue, Yu Zhang, Xianfei He, Henry Q. Li, Sheng Guo. Tim-3 as an immune therapy target, mechanism and action, and prognostic values with its ligands in patient stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 615.