In the past decade, tumor immunotherapy has overturned the traditional concept of treatment, especially the discovery and application of immune checkpoint molecules. The immune checkpoint can be irritating or inhibitory, and the costimulatory protein transmits a signal that promotes an immune response to the pathogen, with the opposite of inhibition. Among them, inhibitory molecular cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) are the two most common immunological checkpoint molecules currently studied. After showing amazing results in the treatment of metastatic melanoma, these two molecules gradually brought new breakthroughs for the treatment of lung cancer, kidney cancer, bladder cancer, head and neck cancer.
More new stimulatory checkpoint molecules now enter into clinical trials, including CD27, CD40, OX40, GITR, ICOS, etc., which usually belong to immunoglobulin or tumor necrosis factor receptor (TNFR) superfamily. Owing to the ability to regulate the innate/adaptive immune cell interactions such as activation, inhibition, and even apoptosis, many members of TNFR superfamily have become targets for tumor immunopharmaceutical research.
1. ICOS (Inducible T-Cell Co Stimulator)
ICOS (Inducible T cell CO-Stimulator) is a homodimeric protein expressed on activated T cells and is expressed only at low levels on dormant primary T cells. ICOS binds specifically to its ligand (ICOS-L), which is normally expressed on dendritic cells and macrophages. In clinical studies, colon cancer patients show a decrease in ICOS, and ICOS expression is associated with higher survival rates in melanoma patients. There are two types of antibodies currently being developed—ICOS agonists and antagonists. Different from agonists that enhance immune function by binding to ICOS, antagonists are mainly to prevent the regulation of ICOS-positive T cell accumulation and inhibit CD4+ infiltrating T cells to secrete Interleukin-10 (IL-10), which eliminates Treg-mediated immunosuppression and may enhance cytotoxic T lymphocyte (CTL)-mediated immune responses against tumor cells, currently used primarily in hematological tumors.
2. OX40 (Tumor necrosis factor receptor superfamily member 4)
OX40 is an activated receptor expressed in cytotoxic T cells and Treg cells and is also a member of the TNFR superfamily, the main immune function of which is to stimulate the proliferation and expansion of CD8+ killer cells and CD4+ helper cells. OX40 receptors are mainly expressed in CD8+ T cells, NK cells, NKT cells or neutrophils, while OX40 ligands are expressed by dendritic cells, B cells, macrophages, and inflammatory sites. Early preclinical studies have shown that OX40 can stimulate anti-tumor effects on tumor immunogenic models including sarcoma, melanoma, and breast cancer, but single-agents have a general effect on weak immunogenic models.
3. GITR (Glucocorticoid-inducedTNFR-related protein)
Glucocorticoid-induced TNFR-related protein (GITR), mainly present in regulatory T cells and CD8 and CD4 lymphocytes activated by TCR, and also in the innate immune system such as NK, macrophages. Similar to OX40, the GITR ligand (GITR-L) is mainly expressed by dendritic cells and is also present in vascular endothelial cells. GITR activates T effector cells, upregulates IL2Rα, produces IL-2 and IFN-γ, and inhibits regulatory T cell function. Early preclinical trials of various solid tumor models have shown that GITR activates the anti-tumor activity of immune cells, especially when combined with other immunomodulatory drugs. At the same time, GITR agonists are also effective for the general low immunogenic model of OX40 stimulation.
4. 4-1BB (CD137, tumor necrosis factor receptor superfamily member 9)
CD137 is an inducible costimulatory cell surface glycoprotein belonging to the TNFR family. It is mainly expressed on the surface of various immune cells, including activated T lymphocytes (CD4+ and CD8+), NK, macrophages, B lymphocytes, etc. T cells can express CD137 through blood, and can also be used to display the specificity of antigens, including tumor antigens. Therefore, CD137 can be used as a surrogate indicator for activated T cells. Preclinical studies have shown that activation of 4-1BB signaling stimulates the action of cytotoxic T cells and NK cells and causes a sustained immune memory response. Due to the diffuse expression of 4-1BB, 4-1BB agonists are prone to systemic adverse reactions.
5. CD40 (Tumor necrosis factor receptor superfamily member 5)
CD40 is mainly expressed in B cells, thymic epithelial cells, activated monocytes/macrophages, dendritic cells, hematopoietic cells, epithelial cells, endothelial cells, and some tumor cells. CD40 ligand (CD40L) is mainly expressed on the surface of CD4+ T cells, including Th0, Th1 and Th2 cell subsets. CD40 mainly functions to induce macrophage activity and then increase cytokine release, and activate T helper lymphocytes when its ligand CD40L is expressed. Although CD40 antibodies have potential efficacy in combination with other anti-tumor drugs, they also have significant toxicity, including cytokine release syndrome, thromboembolic events, and tumor angiogenesis, which may be related to CD40 expression in platelets and endothelial cells.
CD27 is mainly expressed in T cells, B cells, and NK cells. CD70, the ligand for CD27, is mainly expressed in activated T cells, B cells, and mature dendritic cells. The interaction of CD70 with CD27 promotes the activation, proliferation and differentiation of T cells and B cells. Preclinical studies have found that CD27-activated antibodies are effective in activating the anti-tumor immune effects of mice on lymphoma and B16 melanoma.