The prospect of long-lasting responses and the hope of expanding its impact into unresponsive patient populations continue to make immuno-oncology a dynamic and exciting field. As our understanding of the antitumor immune response grows, so does the immunotherapeutic arsenal.
Beyond the CTLA-4 and PD-1 pathways, the targeting of which has proved most fruitful in the clinic, multiple signaling networks are known to be involved in regulating the activation of T cells, the principal effectors of the antitumor immune response. OX40 is among the most promising emerging checkpoints in development.
OX40 is a costimulatory receptor that binds to its only known ligand, OX40L, initiating cellular signaling events required for full activation of T cells following their recognition of a foreign antigen. Agonists that mimic the effect of OX40L can boost OX40 signaling and potentially overcome suppression of the antitumor immune response in patients with cancer.
The clinical development of OX40 agonists is not new, but their distinct and possibly complementary mechanism of action is helping to forge a new path in combination regimens. Clinical trials are testing OX40 agonists in combination with checkpoint immunotherapies, surgical resection, radiotherapy, and even the potential for 3-drug cocktails. Promising reports of preclinical and early clinical data in 2016 are poised to further boost the development of rational combinations.
Activating a Multipronged Attack
Although there are several subsets with distinct roles, the main function of T cells is to coordinate cell-mediated immunity, including the antitumor immune response to malignant cells. Given their potent cytotoxic capabilities, T cells are tightly controlled through a multistep activation process involving a series of receptors expressed on their surface.
First, a T cell must become antigen primed; that is, foreign antigens are presented to the T cell and recognized by its T-cell receptor. Full T-cell activation is then achieved by subsequent costimulatory signals that are generated by the interaction between numerous different receptors on the T-cell surface and their ligands on the antigen presenting cell (APC), facilitated by the formation of close contact between the 2 cells through an immune synapse.
The best-characterized costimulatory receptor is CD28, which is always found on the surface of the T cell and ready to be activated by its ligands, CD80 and CD86, which are located on the APC. Other costimulatory receptors have been identified, including a group that are not automatically expressed but are upregulated following antigen priming. These receptors are thought to provide additional costimulatory signals that are necessary for a long-lasting immune response and for generating immune memory. It is in this group that we find the OX40 protein, also known as CD134.
OX40 is found on the T-cell surface 24 to 48 hours after antigen priming. Like many of the other costimulatory and coinhibitory molecules (the group of receptors that perform the opposing role by deactivating T cells, which includes CTLA-4 and PD-1), OX40 is a member of the tumor necrosis factor (TNF) superfamily of proteins.
Binding of OX40 by OX40L, which is found on the surface of activated APCs, triggers the OX40 signaling pathway. OX40 itself does not have any enzymatic activity; upon activation, it associates with a number of adaptor proteins, including the TNF receptor–associated factors 2, 3, and 5 that activate downstream signaling pathways involving nuclear factor kappa B and c-Jun N-terminal kinase. Ultimately, OX40 signals culminate in enhanced T-cell activation, prolonged T-cell survival, generation of a memory response, prevention of T-cell tolerance, and possibly reduction of the immunosuppressive activity of regulatory T cells.
How to Target OX40
In the absence of any of these activating signals, T cells do not function properly; they fail to proliferate and often become unresponsive, a condition called T-cell anergy, or die. Cancer cells often take advantage of this by increasing the expression of coinhibitory molecules and/or reducing the expression of costimulatory molecules. The cancer cells are thus enabled to co-opt these pathways to subvert the antitumor T cell-mediated immune response.
Several studies have examined the expression of OX40 on T cells that infiltrate the tumor. Although OX40 has been shown to be present on these cells in numerous cancer types, suggesting the T cells have become primed in response to tumor-associated antigens, the expression of OX40L within the tumor is typically low, so the T cells are unlikely to become fully activated. Interestingly, the highest expression of OX40 seems to be on tumor-infiltrating regulatory T cells, which have an immunosuppressive function.