Addressing T cell exhaustion with Network-driven Drug Discovery
Alan V. Whitmore e-Therapeutics PLC, Oxford, UK
T cell anergy and T cell exhaustion are dysfunctional states that characterise the immune response in both chronic viral disease and in cancer. In the case of cancer, tumour cells are able to upregulate the expression of immuno-suppressive ligands that can engage immune checkpoint receptors such as PD-1, TIM-3 and CTLA-4 on the surface of T cells. The combination of antigenic stimulation with such inhibitory signals induces both anergy and ultimately exhaustion and allows tumours to escape from normal immune surveillance.
Clinically it has been shown that inhibition of such negative ligand-receptor interactions with antibodies can overcome anergy and exhaustion in some patients and re-enable an effective immune response. But not all patients respond and not all responders experience sustained benefit. This has led to an interest in combining checkpoint inhibitor therapies. To date such combinations have been explored empirically.
There have been some successes but the number of potential combinations quickly becomes intractable to explore in a clinical situation and there is a need for rational strategies of drug discovery that can help identify not only effective interventions; but in addition, drugs that can be combined with existing standard of care (SoC) agents.
We have used a network-driven drug discovery (NDD) approach to identify two chemical series of drug-like small molecules that are able to modulate checkpoint signalling. These compounds are able to potentiate pro-inflammatory cytokine release from SEB stimulated human PBMCs, can restore the proliferative capacity of experimentally exhausted human CD8 cells and yield increased efficacy in CD3 T cell driven tumour cell killing assays using primary cells from human donors.
The molecules have mechanisms of action that are distinct from those of the existing SoC agents, are active in donors that do not respond to anti-PD-1 and/or anti-CTLA-4 SoC antibodies and are able to potentiate the effects of SoC agents in vitro. Both series are currently undergoing hit to lead optimisation prior to in vivo studies.