Anti-TIGIT therapies for solid tumors: a systematic review

Abstract

Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in cancer treatment, however not all patients benefit from it. Thus new therapies are under investigation, such as anti-TIGIT [anti-T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains] antibodies. TIGIT is an immune checkpoint inhibiting lymphocyte T cells by several mechanisms. In vitro models showed its inhibition could restore antitumor response. Furthermore, its association with anti-PD-(L)1 therapies could synergistically improve survival. We carried out a review of the clinical trial about TIGIT referenced in the PubMed database, finding three published clinical trials on anti-TIGIT therapies. Vibostolimab was evaluated in a phase I alone or in combination with pembrolizumab. The combination had an objective response rate of 26% in patients with a non-small-cell lung cancer (NSCLC) naïve of anti-programmed cell death protein 1 (anti-PD-1). Etigilimab was tested in a phase I alone or in combination with nivolumab, but the study was stopped due to business reasons. In the phase II CITYSCAPE trial, tiragolumab demonstrated higher objective response rate and progression-free survival in combination with atezolizumab than atezolizumab alone in advanced PD-L1-high NSCLC. The ClinicalTrials.gov database references 70 trials of anti-TIGIT in patients with cancer, 47 of them with ongoing recruitment. Only seven were phase III, including five about patients with NSCLC, mostly with combination therapy. Data from phase I-II trials highlighted that targeting TIGIT represents a safe therapeutic approach, with an acceptable toxicity profile maintained when adding anti-PD-(L)1 antibodies. Frequent adverse events were pruritus, rash, and fatigue. Grade 3-4 adverse events were reported in nearly one in three patients. Anti-TIGIT antibodies are under development as a novel immunotherapy approach. A promising research area includes the combination with anti-PD-1 therapies in advanced NSCLCs.

Keywords: TIGIT; immune therapy; lung cancer; tiragolumab.

Figure 1

Mechanisms of TIGIT inhibition in T cells. The TIGIT axis comprises the inhibitory receptors TIGIT and CD112R, as well as the excitatory receptors CD226 and CD96, which mediate a series of engagements with ligands of varying specificity, including PVR (CD155) and poliovirus receptor-related immunoglobulin domain-containing (PVRIG) (CD112). TIGIT displays multiple inhibitory mechanisms in T cells. (1) TIGIT binds to CD155 and delivers intracellular inhibitory signals which in turn reduce TCR expression and TCR signaling. (2) TIGIT binds to CD155 with much higher affinity than its costimulatory counterpart CD226 and thereby can replace CD226 from CD155 binding (3) or disrupts CD226 homodimerization to inhibit CD226-mediated T-cell activation. (4) TIGIT binds to CD155 on APCs to trigger IL-10 production and decrease IL-12 production which indirectly inhibits T cells. (5) Fap2 protein from the gut bacteria Fusobacterium nucleatum, an anaerobic Gram-negative commensal bacteria associated with colorectal carcinoma, binds directly to TIGIT but not CD226 to inhibit NK-cell- and T-cell-mediated tumor reactivity. (6) TIGIT expression on tumor-associated dendritic cells may inhibit CD8 T-cell function indirectly by stabilizing extremely suppressive Tregs. APC, antigen-presenting cell; IL, interleukin; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domain; Treg, regulatory T cell.