TIGIT

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] 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.However, the randomized phase III skyscraper study failed to confirm these results (press release). [16]