TIGIT, or T-cell immunoreceptor with immunoglobulin and ITIM domains, is a protein found on the surface of specific immune cells. As an immune checkpoint, it helps regulate the immune system to prevent it from attacking the body’s healthy cells. In cancer treatment, a new form of immunotherapy using drugs called TIGIT inhibitors is being evaluated in clinical trials. These studies aim to determine if this treatment is safe and effective at helping the body’s immune system fight cancer.
The Role of TIGIT in Cancer Immunity
The immune system has powerful cells, including T-cells and Natural Killer (NK) cells, that can identify and destroy cancerous cells. To prevent these immune cells from becoming overactive, the body uses a system of checks and balances. TIGIT acts as an “off-switch” on these immune cells by binding to a partner protein called CD155, which is often found in high amounts on the surface of tumor cells.
When TIGIT on an immune cell connects with CD155 on a cancer cell, it sends a signal that suppresses the immune attack. This allows the cancer to grow and spread. Cancers exploit this safety mechanism to create a protective shield. By increasing the presence of CD155, tumors engage the TIGIT pathway to evade destruction.
How TIGIT Inhibitors Function in Treatment
TIGIT inhibitors are monoclonal antibodies designed to interfere with this immunosuppressive process. These drugs work by binding to the TIGIT protein on immune cells, which blocks it from connecting with CD155 on cancer cells. By preventing this interaction, the inhibitor “releases the brakes” on the immune system, allowing T-cells and NK cells to recognize and attack the tumor.
A focus of clinical research is testing TIGIT inhibitors in combination with other immunotherapies, especially those that block the PD-1/PD-L1 pathway. The PD-1 protein is another inhibitory checkpoint on T-cells that cancer can exploit. Since TIGIT and PD-1 act as two different braking systems, the rationale is that blocking both simultaneously could produce a more powerful anti-tumor effect. This dual-blockade approach may be effective for patients whose cancers are resistant to a single checkpoint inhibitor, with the goal of creating a synergistic effect.
Key Areas of TIGIT Clinical Research
The investigation of TIGIT inhibitors is active across several types of cancer. Non-small cell lung cancer (NSCLC) is a primary area of this research, with studies exploring TIGIT inhibitors as an initial treatment and for patients whose disease has progressed. Other cancers being studied include small cell lung cancer, head and neck cancers, melanoma, and hepatocellular carcinoma.
Clinical trials are designed to answer specific questions. Some studies focus on patients who have not responded to existing PD-1/PD-L1 inhibitors, investigating if adding a TIGIT inhibitor can overcome this resistance. Other trials evaluate TIGIT inhibitors as a first-line therapy, often combined with chemotherapy and PD-1/PD-L1 blockade, to see if this approach can produce better outcomes.
Some trials enroll patients based on the level of PD-L1 protein in their tumors, as this can predict response to immunotherapy. There are currently dozens of ongoing trials investigating various TIGIT-targeting drugs to identify which patients are most likely to benefit.
Current Status and Notable Trial Outcomes
The journey of TIGIT inhibitors through clinical trials has involved both promise and setbacks. Early studies, such as the CITYSCAPE trial, generated excitement by showing that the TIGIT inhibitor tiragolumab, combined with the PD-L1 inhibitor atezolizumab, improved outcomes in patients with PD-L1-high non-small cell lung cancer (NSCLC). These results positioned TIGIT-targeted therapies as a potential breakthrough.
However, subsequent late-stage trials have delivered sobering results. The SKYSCRAPER series of studies largely failed to meet their primary goals. The SKYSCRAPER-01 trial in PD-L1-high NSCLC did not show a statistically significant improvement in overall survival. Similarly, the SKYSCRAPER-02 trial in small cell lung cancer found that adding tiragolumab provided no additional benefit.
The SKYSCRAPER-06 study in metastatic NSCLC was also halted due to a lack of effectiveness. These outcomes have tempered the initial optimism surrounding TIGIT as a target. Despite these disappointments, research continues, as some data suggests numerical improvements in survival that hint at underlying activity. The field is now focused on understanding these failures and identifying patient subgroups or combination strategies that might still yield a clinical benefit.
Finding and Participating in a Trial
Individuals considering a clinical trial should first discuss the option with their oncologist. An oncologist can evaluate a patient’s cancer type, stage, and treatment history to determine if a trial is a suitable option. They have the most complete understanding of the patient’s medical situation and can provide a referral if an appropriate trial is available.
Reliable online resources can help in the search for clinical trials. The U.S. government maintains a comprehensive database at ClinicalTrials.gov, and the National Cancer Institute (NCI) provides a curated list of cancer trials. Each study has specific eligibility criteria, which may include the type and stage of cancer, previous treatments, and overall health. These criteria are in place to ensure patient safety and the integrity of the research.