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The goal of harnessing the immune system to fight cancer is not new; it dates back 125 years to when William Coley advocated that the body's response to infection could have anti-tumoural effects.1 However, decades of efforts using vaccines and immune stimulant therapies to harness the immune system to fight tumours have had limited success and at times have been fraught with serious adverse outcomes. Recently, drugs blocking negative immune checkpoint pathways have shown remarkable clinical activity in various solid tumours.2 Several agents targeting two such negative checkpoints, the programmed death-1 (PD-1) pathway (pembrolizumab, nivolumab and atezolizumab) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (ipilimumab) are currently Food and Drug Administration and European Medicines Agency approved. These negative checkpoint pathways play a role in immune tolerance in normal tissues and the activation of these pathways is largely contextual. While these therapies have added immeasurably to the longevity of many patients with malignancies, they have come at a cost with the development of numerous untoward autoimmune inflammatory conditions.
The anti-tumour mechanism for checkpoint inhibitor therapies is incompletely understood but clearly relates to the manipulation of T-cell pathways involved in cellular activation and deactivation.2 T-cell homeostasis is a tightly choreographed process whereby naïve T cells rapidly proliferate in a logarithmic fashion when effectively activated and then contract following successful defeat of the challenge. CD4 T-cell activation canonically requires two signals: a primary signal (signal 1), mediated by recognition of cognate antigen by the T-cell receptor via presentation by self-major histocompatibility complex class II molecules on the antigen-presenting cell, and a secondary signal (signal 2), mediated by CD28 on the T-cell, binding its ligand partner of the B7 family on the antigen-presenting cell.3 Of vital importance to the host is the integration of deactivating pathways or checkpoints leading to contraction …