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.
Increasing the number of patients who respond has become a central focus of ongoing research. One promising avenue involves the development of immunostimulatory agonists. Like the block-buster drugs ipilimumab (Yervoy) and nivolumab (Opdivo), this strategy takes aim at the surface receptors that regulate T-cell activity—so-called immune checkpoints (Figure
Whereas ipilimumab, nivolumab, and the growing number of their FDA-approved kin block inhibitory receptors, agonists are designed to activate stimulatory receptors. The endgame is the same: to reignite the antitumor immune response.
Over the past few years, a growing number of immune agonist antibodies with a variety of targets have entered clinical trials. There have been some encouraging responses, but the development of these agents has far outpaced our molecular understanding of how they work—in T cells as well as in other immune and nonimmune cells.
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.
Despite astounding efficacy, just a minority of patients respond, and those who do respond often become refractory to treatment. In hopes of expanding the use of checkpoint therapies and other types of immunotherapy, investigators are looking at stimulatory checkpoint pathways as potential targets.
Table. Selected Clinical Trials of Immune Checkpoint Agonists Under Development
Table. Selected Clinical Trials of Immune Checkpoint Agonists Under Development (Cont.)
To date, agonists have been developed for 7 well-characterized costimulatory receptors for T-cell activation. These drugs are designed to mimic the natural ligands so that they can increase receptor activity and boost the antitumor immune response.
The immune system is often compared to a car: Immune checkpoint inhibitors and stimulatory checkpoint agonists are said to control the gas and brake pedals on the anti-tumor immune response. The endgame is to make the immune system more effective in fighting tumors.2-4
Opinion is Split on OX40
Based on similarity in their structures, costimulatory receptors generally belong to 1 of 2 families: either the tumor necrosis factor receptor (TNFR) superfamily or the immunoglobulin G (IgG) superfamily.