Immune checkpoint inhibitors

An immune checkpoint inhibitor is generally a humanized monoclonal antibody capable of inhibiting an immune checkpoint. Immune checkpoint inhibitors are used as specific therapeutic agents in various tumor diseases. An immune checkpoint inhibitor is generally a humanized monoclonal antibody capable of inhibiting an immune checkpoint. Immune checkpoint inhibitors are used as specific therapeutic agents in various tumor diseases.

The immune system has both costimulatory (activating) and inhibitory (inhibiting) signaling pathways. These regulatory mechanisms influence the strength and intensity of an autoimmune response.

Those signaling pathways with inhibitory effects are called co-inhibitory immune checkpoints and cause down-regulation of T-cell activation or T-cell effector function.

The immune checkpoints with pro-inflammatory effects are called co-stimulatory immune checkpoints.

It is known from tumor diseases that malignant cells are able to recruit immunosuppressive immune cells via activation of co-inhibitory immune checkpoints, as well as upregulate co-inhibitory receptors. Tumor cells use this immunosuppressive effect to escape recognition by the immune system, a phenomenon called immune ev asion.

Knowledge of immune evasion has led to the development of numerous inhibitors of immune checkpoints. These are targeted monoclonal antibodies that are able to block immunosuppressive signals by interrupting this ligand-receptor reaction chain in order to counteract tumor invasion via this immune blockade.

For example, CTLA-4, cytotoxic T-lymphocyte-associated protein 4, is an important checkpoint receptor protein expressed on the surface of T cells. Drugs that reverse tumor-induced inactivation via this checkpoint are called CTLA4 inhibitors.

• Ipilimumab: A checkpoint inhibitor against CTLA-4 is ipilimumab (Yervoy®), which is used to treat advanced malignant melanoma.
• Termelimumab: Termelimumab is also a CTLA4 inhibitor. As a single substance, the study results - for example in malignant melanoma or pleural mesothelioma - were not convincing. The substance is currently being investigated in studies, often in combination with durvalumab.

PD-1 "programmed death 1": Another group of immune checkpoint inhibitors is directed against the immune checkpoint PD-1 "programmed death 1". The protein PD-1 is also expressed on the surface of T cells.

• Nivolumab: Nivolumab (Opdivo®) is a custom-made monoclonal antibody against PD-1. This PD-1 inhibitor is approved for several indications such as malignant melanoma, non-bronchial carcinoma, renal cell carcinoma, classical Hodgkin's lymphoma, squamous cell carcinoma of the head and neck and advanced urothelial carcinoma.
• Pembrolizumab: Pembrolizum (Keytruda®) is another PD1 inhibitor. Pembrolizumab is an antibody used to treat malignant melanoma, non-small cell lung cancer, classical Hodgkin's lymphoma and urothelial carcinoma. Pembrolizumab binds as an antibody to the PD-1 receptor and boosts the body's immune defenses against PD-1 ligand-expressing tumor cells.
• Pidilizumab is also a PD-1 inhibitor that is being studied in patients with lymphoma and pancreatic cancer.

PD-L1 inhibitors - inhibitors of PD-1 ligand, unlike other checkpoint inhibitors - bind directly to the surfaces of tumour cells. PD-L1 is a protein produced by tumor cells and certain macrophages. PDL-1 binds to the immune checkpoint PD1 and leads to its activation. PD-L1 inhibitors prevent this reaction circuit so that the T cells directed against the tumour cells remain active.

• Avelumab (Bavencio®⁾ is an inhibitor of PDL-1. The antibody has so far only been approved as a therapy for Merkel cell carcinoma.
• Atezolizumab (Tecentriq®⁾ is an Fc-part modified humanized monoclonal IgG1 anti-PDL1 (programmed death ligand 1) antibody produced in Chinese hamster ovary cells using recombinant DNA technology. The antibody is approved for patients with urinary bladder cancer and other urothelial cancers, and for patients with non-small cell lung cancer.
• Durvalumab, also a PD-L1 antibody, was approved for the treatment of adults with locally advanced or metastatic urothelial carcinoma.

Ansell SM et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372:311-319.

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