Drugs used in oncology

Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use