TIGIT

TIGIT regulates T-cell mediated immunity via the CD226/TIGIT-PVR pathway.^[11]

During Human Immunodeficiency Virus (HIV) infection, TIGIT expressing CD8+ T cells have been shown to be expanded and associated with clinical markers of HIV disease progression in a diverse group of HIV infected individuals.^[12] Elevated TIGIT levels remained sustained even among those with undetectable viral loads. A large fraction of HIV-specific CD8+ T cells simultaneously express both TIGIT and another negative checkpoint receptor, Programmed Death Protein 1 (PD-1) and retained several features of exhausted T cells.^[12] Blocking these pathways with novel targeted monoclonal antibodies synergistically rejuvenated HIV-specific CD8+ T cell responses.^[12] Further, the TIGIT pathway is active in the rhesus macaque non-human primate model, and mimics expression and function during Simian Immunodeficiency Virus (SIV) infection.^[12] This pathway can potentially be targeted to enhance killing of HIV infected cells during "Shock and Kill" HIV curative approaches.^[13]

TIGIT and PD-1 has been shown to be over-expressed on tumor antigen-specific (TA-specific) CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with melanoma.^[14] Blockade of TIGIT and PD-1 led to increased cell proliferation, cytokine production, and degranulation of TA-specific CD8+ T cells and TIL CD8+ T cells.^[14] It can be considered an immune checkpoint.^[11] Co-blockade of TIGIT and PD-1 pathways elicits tumor rejection in preclinical murine models.^[15] Numerous anti-TIGIT therapies have entered clinical development.

• Tiragolumab

Tiragolumab is the furthest progressed anti-TIGIT therapy in development. In non-small cell lung cancer (NSCLC) setting, the phase II CITYSCAPE clinical trial (NCT03563716) evaluated the combination of the anti-TIGIT antibody tiragolumab in combination with the anti-PD-L1 antibody atezolizumab in patients with newly-diagnosed non-small cell lung cancer whose tumors expressed PD-L1. After a median follow-up of 16.3 months, the combination of tiragolumab and atezolizumab reduced the risk of disease progression or death by 38% compared to atezolizumab monotherapy. In a subset of patients with high PD-L1 expression (at least 50% of tumor cells expressing PD-L1), the combination of tiragolumab with atezolizumab further reduced the risk of disease progression or death by 71% compared to atezolizumab monotherapy. Overall, patients who received the combination of atezolizumab and tiragolumab lived a median of 23.2 months, compared to 14.5 months with atezolizumab monotherapy.^[16] Despite this initial success, there was concern that the benefit of PFS in the tiragolumab + atezolizumab arm was driven by the underperformance of atezolizumab in this trial.^[17] Another concern was that there was no link between TIGIT expression and the efficacy of tiragolumab in the trial.^[18]

The phase III, randomized, double-blinded SKYSCRAPER-01 trial, which evaluates the efficacy of the combination of tiragolumab and atezolizumab in NSCLC patients whose tumors have high PD-L1 expression, failed to show a significant PFS improvement in the combination arm compared with placebo + atezolizumab, although it showed "a numerical improvement" in both endpoints of PFS and overall survival (OS).^[19] In August 2023, an internal PowerPoint presentation detailing OS data of the second analysis was mistakenly made public on the Internet and showed a numerical improvement in terms of OS [estimated overall survival after a median follow-up of 15,5 months: 22,9 months in tiragolumab + atezolizumab arm versus 16,7 months in placebo + atezolizumab arm, HR: 0,81 (95% CI: 0,63, 1,03)].^[20] No new safety signals were identified and the trial remains blinded to investigators and patients.^[21]

Tiragolumab also shows encouraging efficacy in hepatocellular carcinoma setting. In the MORPHEUS-liver trial, tiragolumab + atezolizumab + bevacizumab significantly improved response rate and PFS in both patients with positive PD-L1 expression and with negative PD-L1 expression.^[22]

In small-cell lung cancer, tiragolumab didn't show any OS and PFS benefit in the SKYSCRAPER-02 trial,^[23] but its development in SCLC setting is being continued as consolidation therapy for patients with limited-stage SCLC who have not progressed during/after chemotherapy and radiotherapy (NCT04308785).

In the Skyscraper-04 trial assessing the efficacy and safety of tiragolumab in patients who have recurrent, PD-L1 positive cervical cancer, the combination of tiragolumab and atezolizumab, although improved response rate in both PD-L1 low and PD-L1 high subgroups, only did so marginally and non-significantly.^[24]

The combination of tiragolumab, atezolizumab, and platinum-containing chemotherapy improved PFS and OS compared with comparator arms in esophageal cancer patients in the phase II MORPHEUS-EC trial and the phase III SKYSCRAPER-08 trial.^[25][26]

• T cell receptor
• Antigen