HIV

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]

Cancer

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 humans, the 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 were concerns that the benefit of PFS in the tiragolumab + atezolizumab arm was driven by the underperformance of atezolizumab in this trial.^[17] The phase III, randomized, double-blinded SKYSCRAPER-01 trial failed to meet the first endpoint of PFS, although it showed "A numerical improvement" in both endpoints of PFS and overall survival (OS).^[18] In August 2023, an internal PowerPoint presentation, which details 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)].^[19] No new safety signals were identified and the trial remains blinded to investigators and patients.^[20] 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.^[21] In small-cell lung cancer, tiragolumab didn't show any benefit in terms of OS and PFS in the SKYSCRAPER-02 trial,^[22] 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)