When it works, immunotherapy can dramatically outperform standard of care—for some cancer types, in ways thought unattainable a decade ago. Yet immunotherapy works in just a minority of patients, and some tumor types are particularly resistant.
This knowledge gap has led to disappointing outcomes and discontinuation of some clinical programs. However, clinical experience over-whelmingly demonstrates that immune agonists have great potential if the kinks can be worked out. This is particularly true of their use in rational drug combinations, in which they have the potential to prime the antitumor immune response and even help turn immunologically “cold” tumors into “hot” tumors that are more responsive to immunotherapy.
The T-Cell Activation Mechanism
T cells are the central mediators of adaptive immune protection and are endowed with potent cytotoxic capabilities. Accordingly, their activity is tightly regulated through a multistep process coordinated by a series of receptors expressed on their surface.
The first step is for T cells to become primed by foreign or altered self-antigens that are displayed on major histocompatibility complex 1 molecules on the surface of antigen-presenting cells (APCs). These antigens are recognized by the receptor on the surface of the T cell.
Figure. Immune System Presents Many Opportunities for Targeting Cancer
A secondary antigen-independent signal is then generated by the interaction between numerous other receptors on the T-cell surface and their ligands on the APCs, collectively referred to as immune checkpoints. The binding of a ligand to its respective receptor propagates a signal within the T cell that is ultimately either stimulatory or inhibitory.
A stimulatory signal acts like an on switch, driving full activation of the T cell. In the absence of this signal or in the presence of an inhibitory one, T cells fail to proliferate and become unresponsive or die. This dual signal mechanism ensures that the amplitude and duration of the T cell–mediated immune response is tightly controlled, but the downside is that it can also be exploited by cancer cells to dysregulate the anti-tumor immune response.
Step on the Gas
In the past decade, drugs targeting the inhibitory receptors have emerged as an important form of immunotherapy because they can help activate T cells and restore antitumor immunity. A host of immune checkpoint inhibitors are now FDA approved for a growing number of indications.
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