Release Date: 04-Oct-2023
Through years of research to find the most effective and safe treatment interventions for treating cancer, investigators have identified several immune checkpoints over the years that are now understood to exert an inhibitory effect on the immune system that disables it from eliminating cancer cells. One of the most recently discovered of these is the TIGIT, or T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains, which was identified in 2009. TIGIT is a co-inhibitory molecule belonging to the immunoglobulin superfamily and is expressed exclusively on lymphocytes. Its role as an immune suppressor has shed light on its potential to be regarded as a protein of interest for the development of novel therapeutics to block its inhibitory effects.
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Several ligands of TIGIT have been identified till date; however, TIGIT shows the highest affinity for CD155, which interacts with TIGIT on NK cells and mediates inhibitory immunomodulatory regulation. CD155 is upregulated on a number of cancer cells and affects biological functions such as cell adhesion, migration, invasion and proliferation. It therefore plays a carcinogenic role. On contrary, the binding of CD155 with CD226 results in a co-stimulatory action, which can be blocked by TIGIT by actively competing with CD226 to bind with CD155. Therefore, TIGIT can suppress immune cells through multiple pathways, which only increase as we consider its interactions with its multiple ligands and their downstream consequences. These only provide further evidence of using TIGIT as a target for therapeutics like antibodies and small molecule inhibitors.
Inhibition of PD-1/L1 was one of the first immunotherapy strategies developed for treating cancer. This treatment approach was highly success in a sizeable number of patients. However, in certain cancers like colorectal carcinoma, treatment with PD-1/L1-blocking molecules resulted in durable response in only a subset of people, making the therapy ineffective. Through a number of research studies, it was later revealed that the TIGIT protein was involved in this. Using a series of inhibitory receptor-ligand interactions, TIGIT contributed to the development of resistance in cancer patients undergoing treatment with a PD-1/L1 blockade. Therefore, dual inhibition of TIGIT and PD-1/L1 could act as a possible tactic to overcome this barrier.
Further preclinical and clinical trials demonstrated that the co-blockade of PD-1/L1 and TIGIT resulted in antitumor immune response of a further grade when compared to PD-1/L1 blockade alone, providing the proof of concept for the aforementioned hypothesis, and also establishing a successful strategy for the treatment of cancer patients resistant to PD-1/L1 blockade therapy. An immune response of a similar level was achieved when PD-1/L1 was blocked with another immune checkpoint protein CTLA-4; however, this resulted in adverse effects of varying degrees, which still limits their combined use in clinical settings. Hence, TIGIT emerges as a promising combinational partner for PD-1/L1 when compared to other checkpoint proteins.
TIGIT is expressed on tumor-infiltrating NK cells; the net balance of activating and inhibiting signals received by its receptors regulates the functions of NK cells. As mentioned above, the interaction of CD155 with CD226 results in a co-stimulatory signal, while the binding of CD155 with TIGIT results in immune suppression. Therefore, an increase in TIGIT expression on NK cells can lead to functional exhaustion of NK cells. Moreover, in the B16 melanoma mouse model, the deficiency of TIGIT on NK cells improved the survival of mice. In addition, a lower number of tumor-infiltrating CD8+ T cells expressing TIGIT and TIM3 were observed, which led to the observation that TIGIT-expressing NK cells also contribute to the exhaustion of CD8+ T cells.
Along with the B16 melanoma mouse model, the prospects of TIGIT inhibition has been supported by results from several other animal cancer models, which shows the potential of TIGIT inhibition in a number of cancers. In the CT26 colon carcinoma mouse model, blockade of TIGIT inhibited tumor growth and prevented exhaustion of tumor-infiltrating NK cells. In a hepatocellular carcinoma mouse model, the co-blockade of PD-1/TIGIT resulted in a synergistic inhibition of tumor growth and significantly prolonged mice survival. In the MC38 mouse model of colon carcinoma, TIGIT blockade alone led to a small but uniform retardation of tumor growth. Therefore, researchers have multitudes of data now that support the use of TIGIT inhibitors as both monotherapy and combination therapy for the treatment of many different cancers.
Research from animal models and preclinical studies have translated into clinical trials, with several candidates now undergoing clinical trials in humans. A number of these products have also begun phase III clinical studies. Though, no TIGIT inhibitor is in market as of now, promising results from ongoing clinical trials support the use TIGIT inhibitors in various cancers. Tiragolumab, Domvanalimab, MK-7684, COM902, IBI-939 and AZD2936 are some candidates in development. TIGIT inhibitors are being developed as both monospecific and bispecific antibodies, and both are combined with an array of investigational and approved anticancer drugs.
Roche is developing the anti-TIGIT monoclonal antibody Tiragolumab to prevent TIGIT from interacting with the poliovirus receptor (PVR). Tiragolumab is in phase III clinical trials as a first-line treatment of non-squamous non-small cell lung cancer and esophageal cancer. Gilead Sciences and Arcus Biosciences are co-developing Domvanalimab, another TIGIT inhibitor in phase III clinical trials for non-small cell lung cancer and gastrointestinal tract adenocarcinoma. Similarly, Merck’s MK-7684A, a co-formulation of Vibostolimab (anti-TIGIT) and Pembrolizumab (anti-PD-1), is in late-phase trials for lung neoplasms and melanoma.
Though these are only a few cancer indications that are being treated using anti-TIGIT monotherapies and combination therapies, the prospect of TIGIT antibodies encompass a variety of cancers like liver cancer, pancreatic cancer, breast cancer, colorectal cancer, gallbladder cancer and glioblastoma as reported from several animal and preclinical studies. Recent studies have also shown TIGIT to be involved in the regulation of B cells, and the development and maintenance of B-cell cancers like lymphoma, chronic lymphocytic leukemia and follicular lymphoma.
The potential of TIGIT inhibitors in all these cancers, which have huge patient bases globally, shows that we are yet to realize the full potential of TIGIT blockade. Anti-TIGIT antibodies seemingly find use in a number of cancer indications and have an unforeseeable scope for the future. Moreover, as observed in animal models, combination of anti-TIGIT antibodies with existing immunotherapies and anticancer therapies can be used to enhance the immune response towards cancer cells, thereby increasing the efficacy of treatment, though in doing this, safety cannot not be compromised. The future holds immense potential for TIGIT antibodies, and research and pharmaceutical companies are on their way to grasp the clinical and commercial aspects of TIGIT blockade in cancer.
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