Do We Need Small Molecule Inhibitors for the Immune Checkpoints?

Abstract

Pharmaceutical Care & Health SystemsT lymphocytes preserve the immunological balance between defending against cancer and preventing continual activated immune responses. The balance between the two extremes requires an intricate network of protein-protein interactions (PPIs) that can either inhibit T cell-mediated immune responses targeted against self-antigens or stimulate them to defend against cancer [1]. While T cells' specificity against cancer is determined by the interaction between the T-cell receptor complex (TCR) and antigenic peptides bound in surface major histocompatibility complex (MHC) molecules, the full activation of T cells requires a second signal obtained by the binding of the co-receptor CD28 on T cells to CD80/86molecules on activated antigen presenting cells (APCs). Once mobilized, T cells also express other receptors that inhibit their proliferation and cytokine production. Among these receptors are three immune inhibitory checkpoints: Cytotoxic T Lymphocyte Antigen-4 (CTLA-4), programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3). Tumors can evade the immune system via inhibitory checkpoints to attenuate T cells' signaling, leading to a state of immune tolerance [2]. Blocking the immune inhibitory checkpoints pathways recently emerged as a 'game changer' approach in cancer immunotherapy [3][4][5], with antibodies directed toward PD-1, for example, being selected as 'drug of the year' for 2013 by Science6. These antibodies proved the concept of restoring exhausted T cells' functions and reactivating the immune system to recognize and kill tumor cells [6,7]. More importantly, combination blockage of multiple co-inhibitory pathways has a greater efficacy by preventing accumulation of the unblocked negative co-receptor, allowing T cells to continue to survive, proliferate, and carry out effector functions within the tumor [8][9][10][11][12][13][14][15][16]. However, despite their outstanding success, they still have numerous disadvantages. These agents are monoclonal antibodies and are very expensive to manufacture and administer, making them financially inaccessible to many. For example, under current market conditions, the treatment cost per quality-adjusted life year (QALY) for a patient with metastatic melanoma exceeds $500 000 (USD). These antibodies require bolus intravenous injections every 3 weeks, are administered in high dose and have a long half-life. They cannot be quickly withdrawn from the body if adverse events occur (such as autoimmunity) [17,18]. For example, treatment with antibodies targeting CTLA-4 results in life-threatening autoimmune colitis in 5-10% of patients46 and treatment-related fatalities, while rare, continue to be reported. These limitations suggest that the full potential of the immune checkpoint blockade has yet to be fulfilled and raise an urgent need to explore new modalities that can target the same pathways, but be safer and more effective.Small molecules can provide this safe therapeutic alternative. They can avoid the problems associate...

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