Immuno-oncology – often abbreviated to ‘IO’ – is one of the most dynamic and exciting fields of ongoing cancer research. What makes IO treatments unique is that they empower the patient’s immune system1to specifically recognise and attack cancer cells.
Several IO drugs have recently been approved for use in multiple tumour types, and have already changed the treatment landscape for cancer patients around the world. Here at AstraZeneca and MedImmune, we have a number of IO therapies in our oncology pipeline. In this article, I would like to discuss one of our key targets for IO, known as OX40.
OX40 and the T-cell response
T cells are a key mediator of the immune response to a tumour. In the normal course of events, antigens from the tumour are presented to T cells, stimulating the immune system to attack malignant cells. For this process to work most efficiently, full T-cell activation is needed which, in turn, requires multiple independent signals: an antigen-specific signal generated by the T-cell receptor, a second signal through CD28 and subsequent additional co-stimulatory signals. When T cells are stimulated through an antigen receptor and CD28 without subsequently receiving sufficient co-stimulation, the cells are unable to sustain proliferation and often become unresponsive or die.2
For an optimal and long-lasting T cell response, additional ‘co-stimulatory’ signals are required. This is where OX40 comes in.
As shown in the infographic below, OX40 is a protein receptor expressed on the surface of activated T cells that have been exposed to antigens, such as those from tumour cells.3 Binding and clustering of OX40 by OX40 ligand, typically expressed on activated antigen-presenting cells, triggers this co-stimulatory receptor signalling pathway.4
Activation of OX40 may have several important outcomes, including:5
- Prolonged T-cell survival and memory generation
- Prevention of T-cell tolerance
- Reduced immunosuppression by regulatory T cells
Targeting OX40 to enhance anti-tumour immune response
A group of investigational therapies known as ‘OX40 agonists’ have been designed to exploit this co-stimulatory pathway. These drugs bind to and activate OX40, in a similar manner to OX40 ligand binding to OX40, and may therefore enhance T-cell stimulation, reduce T-cell tolerance, and promote tumour killing by the immune system.
At AstraZeneca and MedImmune, our investigational OX40 agonist is known as MEDI0562. We recently presented preliminary data of a Phase 1 study of monotherapy MEDI0562 conducted in adults with advanced solid tumours. Results were discussed this week at the European Society for Medical Oncology (ESMO) Annual Congress in Copenhagen.
Furthermore, another Phase 1 trial is now ongoing, in which MEDI0562 is combined with other IO drugs in our pipeline. These include combinations with durvalumab (which blocks signals from PD-L1 that help tumours to avoid detection by the immune system6) and tremelimumab (which blocks the activity of CTLA-4, an inhibitory molecule that regulates T-cell activation7).
Of course, these are early days, and larger trials will of course be required before these investigational products can be approved as anti-cancer therapies. However, based on pre-clinical data, we are excited by the potential enhanced anti-tumour activity offered by these combination approaches.
- European Cancer Patient Coalition. (2016). What is immuno-oncology? A guide for patients. Available at: www.ecpc.org/Documents/Policy&Advocacy/Immuno-Oncology/Event%2019th%20Nov%202014/IO%20patients%20leaflet.pdf. Accessed September 2016.
- Frauwirth & Thompson. (2002). Activation and inhibition of lymphocytes by costimulation. J Clin Invest 109:295-9.
- Weinberg et al. (2011). Science gone translational: the OX40 agonist story. Immunol Rev 244:218-31.
- Linch et al. (2015). OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol 5:34.
- Gao et al. (2013). Advances in the development of cancer immunotherapies. Trends Immunol 34:90-8.
- Stewart et al. (2015). Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 3:1052-62.
- Parry et al. (2005). CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543-53.