A new class of cancer treatments, known as anti-TIGIT therapy, is emerging within the field of immunotherapy. This approach does not attack cancer directly but is designed to empower a patient’s own immune system to fight the disease more effectively. Researchers are investigating how these treatments can overcome resistance to existing immunotherapies. By focusing on a specific interaction between immune cells and cancer cells, this therapeutic strategy offers a targeted way to boost the anti-tumor immune response.
The TIGIT Pathway as an Immune “Brake”
The immune system has protective measures, often called checkpoints, to prevent it from becoming overactive and damaging healthy tissues. These checkpoints function like a car’s braking system, ensuring that immune responses are controlled. The immune system’s T cells are responsible for identifying and eliminating threats, including abnormal cells. These T cells have various proteins on their surface that can either press the “gas” or the “brake” on an immune attack.
One of these braking mechanisms involves a protein called TIGIT, which stands for T-cell immunoreceptor with Ig and ITIM domains. TIGIT is a receptor found on the surface of immune cells, including T cells and natural killer (NK) cells. When TIGIT is activated, it sends an inhibitory signal into the T cell, telling it to halt its aggressive actions. This is a normal process that helps maintain balance within the immune system.
Cancer cells have developed ways to exploit this natural braking system. Many tumor cells display high levels of a corresponding protein on their surface called the poliovirus receptor (PVR), also known as CD155. When the PVR on a cancer cell binds to the TIGIT receptor on a T cell, it pushes the T cell’s brake pedal. This interaction signals the T cell to stand down, creating an immunosuppressive tumor microenvironment that allows cancer to evade the immune system’s attack.
Mechanism of Anti-TIGIT Action
Anti-TIGIT therapies are a type of drug known as a monoclonal antibody, which is a lab-engineered protein designed to bind to a specific target. In this case, the target is the TIGIT protein on immune cells. The action of an anti-TIGIT antibody is to physically block the TIGIT receptor, preventing it from interacting with ligands like PVR that are present on tumor cells.
By obstructing the TIGIT receptor, the therapy prevents the inhibitory signal from being sent into the T cell. This action “releases the brakes” on the immune cell, restoring its ability to recognize and attack malignant cells. The therapy itself does not kill cancer cells directly but enables the immune system to perform its natural function more effectively.
This mechanism also affects a related pathway. T cells have another surface receptor called CD226, which functions as an accelerator for the immune response. TIGIT and CD226 compete to bind to the same PVR ligand on tumor cells. By blocking TIGIT, anti-TIGIT antibodies allow CD226 to bind with PVR, which promotes the activation and function of T cells and NK cells against the tumor.
Role in Combination Therapies
While anti-TIGIT therapies can function on their own, they are most frequently studied as part of a combination treatment strategy. Much of the research focuses on pairing anti-TIGIT drugs with another class of checkpoint inhibitors that target the PD-1/PD-L1 pathway. The PD-1 receptor is another inhibitory “brake” on T cells, and cancer cells can express the PD-L1 ligand, which binds to PD-1 and suppresses the T cell response.
The rationale for combining these therapies is based on synergy. TIGIT and PD-1 represent two distinct braking systems that tumors exploit. Blocking only one of these pathways may not be enough to fully reactivate a T cell, as the other can still transmit inhibitory signals. By administering both an anti-TIGIT and an anti-PD-1 drug, clinicians aim to release two separate brakes on the immune system at once.
This dual blockade is hypothesized to produce a more powerful and durable anti-tumor response than could be achieved with either therapy alone. Preclinical studies have shown that combining these treatments leads to greater tumor regression. This approach appears to enhance the function of the CD8+ T cells that are responsible for killing cancer cells. Because exhausted T cells in a tumor often express multiple checkpoint receptors, a multi-pronged attack may be necessary to restore their function.
Clinical Trials and Targeted Cancers
Anti-TIGIT therapies are investigational and are accessible to patients through participation in clinical trials. These studies are necessary for determining the safety and effectiveness of these new drugs. A significant portion of this research evaluates anti-TIGIT antibodies when used with other immunotherapies, particularly anti-PD-1 or anti-PD-L1 agents.
Several types of cancer are the focus of these clinical investigations, based on biological rationale and early trial data. Non-small cell lung cancer (NSCLC) is a major area of study, with multiple large-scale trials underway. Other cancers being actively explored include:
- Small cell lung cancer
- Melanoma
- Esophageal cancer
- Various other solid tumors
A few prominent anti-TIGIT drugs in development include tiragolumab, domvanalimab, and vibostolimab. For instance, the phase II CITYSCAPE trial showed that combining tiragolumab with an anti-PD-L1 therapy improved response rates in patients with advanced NSCLC. Similarly, domvanalimab has shown a survival benefit in a lung cancer study when paired with an anti-PD-1 inhibitor.
The path of clinical development has seen mixed results, which is common for new drugs. While some studies have produced promising data, others have failed to meet their goals, leading to the discontinuation of certain trials. This highlights the complexities of cancer immunotherapy and the ongoing effort to identify which patients and cancer types are most likely to benefit from this approach.