As researchers continue to identify a growing number of immune checkpoints as targets for anticancer therapy, the recently discovered TIGIT pathway is emerging as a promising new avenue for exploration.
TIGIT is a poliovirus receptor (PVR)–like protein, an immunoreceptor expressed on T cells that contains immunoglobulin (Ig) and immunoreceptor tyrosine–based inhibitory motif (ITIM) domains. As such, TIGIT acts as an inhibitory immune checkpoint on both T cells and natural killer (NK) cells, providing an opportunity to target both the adaptive and innate arms of the immune system.
Although clinical development is in preliminary stages, TIGIT and related proteins show significant therapeutic promise, particularly in combination with other immune checkpoint inhibitors, with the potential to broaden the benefit of immunotherapy into previously unresponsive patient populations.
Genentech has launched a phase I trial evaluating MTIG7192A, a fully human monoclonal anti- body that binds to TIGIT and prevents its interaction with PVR. The trial, which opened in June, will evaluate the safety and efficacy of MTIG7192A as monotherapy and in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) in a 2-step study that aims to enroll 300 patients with locally advanced or metastatic tumors (NCT02794571).
In September 2016, Bristol-Myers Squibb initiated a phase I/II study of an anti-TIGIT monoclonal antibody, BMS-986207, as monotherapy and in combination with nivolumab (Opdivo) in advanced solid tumors (NCT02913313). The estimated enrollment for the trial is 170 participants.
Compugen Ltd is developing COM701, an antibody that targets PVRIG, another recently elucidated member of the PVR family. The company is planning to submit an Investigational New Drug application to the FDA during the fourth quarter of 2017.
Where TIGIT Fits In
The major effectors of the immune system are cytotoxic T cells, and these are activated in a 2-step process when they encounter antigen-presenting cells bearing foreign antigens. Antigens engage the T-cell receptor (TCR) on the surface of the T cell, but this signal is coupled with a second signal that determines whether the T cell is turned on or off. Together these costimulatory and coinhibitory signals are known as immune checkpoints.
CTLA-4 and PD-1, the most successful immune targets for anticancer therapies, generate coinhibitory signals. Since cancer cells and the cells of the surrounding microenvironment have been shown to upregulate the expression of components of their respective pathways as a means of suppressing the antitumor immune response, the development of antibodies that block their activity has been embraced by immuno-oncologists in the hopes of reversing these suppressive effects.
The anti–PD-1 antibodies nivolumab and pembrolizumab (Keytruda) and the PD-L1–targeting agent atezolizumab have been approved in multiple malignancies while ipilimumab (Yervoy) remains the only CTLA-4 inhibitor on the market.
TIGIT is among the novel coinhibitory immune checkpoints under study (Table
). It was first identified about a decade ago in a genome-wide screen- ing for potential immune inhibitory proteins. Researchers were searching for proteins that were expressed by immune cells and that contained an ITIM domain, which is known to mediate immune cell deactivating signals. TIGIT is a member of a recently discovered arm of the Ig superfamily, the PVR-like proteins, which contain PVR motifs in their Ig variable-like domain.
Further investigation revealed that TIGIT was reminiscent of the CTLA-4 protein, in that it shares ligands with an activating receptor. CTLA-4 is activated by binding to the B7-1 and B7-2 (also known as CD80 and CD86, respectively) proteins. These proteins also serve as ligands for the CD28 protein, a costimulatory molecule; thus the activating and deactivating receptors compete for the same ligand, with a delicate balance determining if the T cell is switched on or off.
The ligand for TIGIT is CD155 (alternatively known as PVR), but this protein also serves as a ligand for CD226, which, like CD28, is an activating receptor. When CD155 is bound to CD226, it conveys activating signals into the immune cell. Meanwhile, CD155 bound to TIGIT transmits an inhibitory signal by recruiting the SHP1 phosphatase to the membrane through its ITIM domain that subsequently deactivates numerous proteins involved in T-cell effector functions.
A third member of the PVR-like protein family, CD96 (sometimes referred to as T cell-activated increased late expression [TACTILE]), also binds to CD155. The function of this interaction is not yet understood, although mouse CD96 has been shown to be involved in inhibitory signaling like TIGIT.
Meanwhile, although TIGIT binds most strongly to the CD155 protein, it also partners with another ligand, CD112, with lower affinity, adding to the complexity of this pathway. Furthermore, PVRIG (known as CD112R), another newly discovered member of the PVR-like family, also binds to CD112.