Discovered in 2000 by a team working across Harvard Medical School, Boston and Kyoto University programmed death 1-ligand 1 (PD-L1) (link is external) is now the target of a new wave of cancer drugs. It is found on antigen presenting cells, such as macrophages, B lymphocytes and dendritic cells, and interacts with the PD-1 receptor on T-cell lymphocytes. This molecular match serves as an immune checkpoint to switch off T-cell activity and prevent the immune system attacking the body’s own cells. Since its discovery the PD pathway has been shown to be important in autoimmunity, infectious immunity, transplantation immunity and allergy. However, clinically, interest around this immune checkpoint stems from the potential to block its activity and create a targeted tumour immunotherapy.
Numerous immune checkpoints exist, where proteins on the surface of activated T cells interact with their ligands on antigen presenting cells to reduce T cell function. T cell activity is limited in this way to stop the killing of bystander host cells during an infection and to control autoimmunity. The discovery that some tumours express immune checkpoint molecules, like PD-L1, shows how they can avoid detection and destruction by the immune system. Using antibodies to block the PD-1 / PD-L1 interaction can prevent the cancer cells from evading T cell function in this way, and this approach is proving very effective in the clinic.
The pursuit of cancer treatments that work through alerting the immune system to their presence is not new. Previous efforts have included stimulation with cytokines to activate T cells and intra-tumour injections of bacterial products to induce inflammation, which will recruit an anti-inflammatory response. Despite years of research these attempts have met with limited success. Most studies report a maximum response rate of 10% when tested in patient cohorts.
The underlying principle of previous approaches to cancer immunotherapy was that they attempted to activate the immune system in order to create a greater response to the tumour. But the stimulation of T cells is quickly overcome in the body by the release of interferon. This increases the expression of PD-L1 by tumour cells, allowing them to shut down the T cell response against the tumour. It seems that the limiting step in targeting cancer immunotherapies is not turning on the immune system against the cancer, but avoiding the activation of the brakes of the immune system by immune checkpoints.
Within the clinic antibodies targeted to PD-1 and PD-L1 are showing remarkable results. This form of immunotherapy appears to shrink tumours in a higher number of patients across a wider range of tumour types and is associated with lower toxicity levels than other immunotherapies. Compared to the previously acknowledged ceiling of 10% patient response rates for immunotherapy approaches to cancer, treatment with inhibition of PD-1 and PD-L1 are showing responses in between 25 and 40% of patients. Although many of the trials are fairly recent one of the most notable features of immune checkpoint inhibition appears to be the durability of the patient response (link is external), with patients living much longer than with other standard cancer treatments, such as chemotherapy.
Smaller tumours appear to respond better to anti-PD-1 or anti-PDL1 therapy and so the best results may be achieved by using these PD pathway inhibitors as part of a combination of therapies, with radiotherapy or chemotherapy, may offer the best results. Part of the issue may be the large size of the antibody being unable to penetrate solid tumours, whereas shrinking the tumour with other approaches before immune checkpoint immunotherapy could avoid this. Treating patients firstly with radiation or chemotherapy may release tumour antigens from the dead tumour cells, making the tumour more visible to the immune system.
As the reported patient benefits of these PD1 and PD-L1 inhibitors increase it may appear as though at this point we have adequately targeted the pathway. However, studies show that significantly more antitumor activity is possible using a small-protein therapeutic (link is external)compared with a conventional antibody. The drawbacks associated with antibodies include their large size and their ability to activate antibody dependent cell-mediated cytotoxicity, through their Fc-region. While Fc-mediated effects are an important part of the efficacy of many antibody therapeutics, in the case of PD-1 / PD-L1 inhibition this may be counterproductive. As PD-1 and PD-L1 are expressed on the surface of T cells targeting these proteins could result in an unwanted reduction of these anti-tumorigenic cells. In the clinic, treatment with these immune checkpoint inhibiting antibodies has been associated with lower T cell numbers (link is external) in patients.
To understand how we have used Affimer technology to rapidly generate a pool of high quality PD-L1 inhibitors and are formatting these for use as biotherapeutics to tackle cancer, access our webinar below.