Potential partner for immune checkpoint inhibitors-TIM3 inhibitors

T cell immunoglobulin mucin-3 (TIM3) was first discovered in 2002 and is a member of the TIM family of immunomodulatory proteins. TIM3 has attracted much attention because it is related to the regulation of autoimmunity and immune response in cancer. In recent years, the development of TIM3 inhibitors is also steadily proceeding, with a view to solving the problems of low response rate and drug resistance of existing immune checkpoint inhibitors.

Immunosuppressive drugs effect of TIM3 in tumor microenvironment

TIM3 was originally thought to be a receptor expressed on CD4+ and CD8+ T cells that produce interferon-γ, and TIM3 expression was subsequently found in many other types of cells, including regulatory (Treg) T cells , Myeloid cells, natural killer cells and mast cells. Therefore, TIM3 targeted therapy may modulate the immune response by acting on multiple cell types.

TIM3 can inhibit T helper cells (Th1 and Th17) in the tumor microenvironment, induce CD8+ T cell depletion, promote Treg cells to become a highly immunosuppressed cell population, and promote bone marrow-derived cells with powerful T cell immune response suppression functions. A large number of inhibitory cells (MDSCs) expand, promote innate immunosuppression, and tumor immune escape.

The specific role of TIM3 in non-T cell leukocytes is summarized in the following table:

Advances in clinical research of TIM3 block therapy

In the preclinical model, the combined blocking therapy of TIM3 and PD1 is superior to monotherapy, which can improve the anti-tumor T cell response of patients with advanced cancer and can lead to tumor regression.

Recently, a number of clinical trials of TIM3 blocking therapy alone or in combination with other therapies have been carried out (one of which is a clinical trial of bispecific antibodies designed for PD-1 and TIM3), involving many types of tumors. Advanced malignant tumors, such as acute myeloid leukemia (AML), lymphoma, liver cancer, and non-small cell lung cancer, are summarized in the following figure:

Ongoing and planned clinical trials of anti-TIM3 drugs
(Picture from reference 2)

TSR-022 is the first anti-TIM3 drug to publish experimental data. This is a humanized anti-TIM3 IgG4 antibody developed by Tesaro. Monotherapy with TSR-022 resulted in 31 patients with stable disease (SD), 1 patient with leiomyosarcoma had partial response (PR), and no dose-limiting toxicity was observed.

The effectiveness of TSR-022 single drug has opened the door to hope for subsequent combination therapy with PD-1 antibody. In 202 cases of non-small cell lung cancer patients refractory to PD-1/PD-L1 antibody, when used in combination with a fixed dose of TSR-042 (a PD-1 antibody), as the dose of TSR-022 increased Its clinical activity is also increasing (represented in the proportion of SD or PR patients). Most importantly, this combination therapy is also well tolerated, with no dose-limiting toxicity observed.

Recently, Eli Lilly’s TIM3 blocking antibody LY3321367 and Novartis’ anti-TIM3 antibody MGB453 have been reported to have successfully passed Phase I clinical trials. Consistent with the preclinical model, the combined blocking therapy of TIM3 and PD1 is superior to monotherapy.

These existing data indicate that TIM3 is indeed a “checkpoint” receptor. Inhibiting TIM3 can enhance the anti-tumor effect of PD-1 blockers, and is expected to become the next strength partner of PD-1 block therapy for tumor patients. Bring more treatment options and hope. I also hope that these ongoing clinical trials will bring us more good news.

references:

[1] Tao Jinglian, Li Lijuan, Shao Zonghong. Research progress of the role of TIM3 in tumor microenvironment [J]. Chinese Journal of Immunology, 2016, 32(7):1070-1073.

[2] Wolf Y, Anderson A C, Kuchroo V K. TIM3 comes of age as an inhibitory receptor[J]. Nature Reviews Immunology, 2019: 1-13.

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