Abstract
Programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) blocking therapy has completely changed the treatment pattern of malignant tumors. It has been tested in a wide range of malignant tumors and achieved clinical success. It might be a promising cancer treatment strategy. However, one of the important disadvantages of PD-1/PD-L1 blocking therapy is that only a few patients have a positive response to it. In addition, primary or acquired drug resistance can also lead to cancer recurrence in patients with clinical response. Therefore, it is very important to overcome the resistance of PD-1/PD-L1 blocking therapy and improve the overall response rate of patients to the immunotherapy. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) belongs to the co-inhibitory receptor family involved in immune checkpoint function. Due to adaptive resistance, the expression of Tim-3 is up-regulated in PD-1/PD-L1 blocking therapy resistant tumors. Therefore, blocking the immune checkpoint Tim-3 might antagonize the resistance of PD-1/PD-L1 blocking therapy. This review systematically introduces the preclinical and clinical data of combined blockade of Tim-3 and PD-1/PD-L1 in cancer immunotherapy, and discusses the prospect of overcoming the drug resistance of PD-1/PD-L1 blockade therapy through blockade of Tim-3.
Highlights
Co-inhibitory receptors play the following important roles in cells: regulating T cell response and maintaining immune homeostasis [1]
T cells express a variety of co-inhibitory receptors: CTLA-4, Programmed death receptor 1 (PD-1), Tim-3 (T cell immunoglobulin and mucin containing protein 3 or CD366), TIGIT (T cell immune receptor with immunoglobulin and ITIM domains), LAG-3 and Vista (T cell activation inhibitor containing V domain immunoglobulin) [2,3,4]
To extend these results and determine their applicability to patients treated with anti-PD-1 antibodies, specimens from two patients who showed an initial response to PD-1 blockade but developed progressive disease were analyzed. These cases exhibited similar upregulation of Tim-3 on therapeutic antibody-bound TILs. These results suggest that targeting alternate immune checkpoints such as Tim-3 upregulated in the context of PD-1 therapy may extend the benefit of PD-1 blockade in responsive tumors [87] (Figure 1)
Summary
Co-inhibitory receptors play the following important roles in cells: regulating T cell response and maintaining immune homeostasis [1]. To determine whether blockade of Tim-3 at the time of resistance might be therapeutically efficacious, TIM-3-blocking treatment in these mice were performed and demonstrated a clinical benefit To extend these results and determine their applicability to patients treated with anti-PD-1 antibodies, specimens from two patients who showed an initial response to PD-1 blockade but developed progressive disease were analyzed. Two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy [88] It suggested that sabatomimab combined with spartalizumab was well tolerated and showed preliminary signs of antitumor activity. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies
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