Interest Builds for Targeting TIGIT Checkpoint

TIGIT, an inhibitory immune checkpoint that plays a central role in limiting antitumor responses, is attracting robust interest in the research community as a novel target for combination therapies across a range of cancer types, particularly solid tumors.

Clinical trials of antibodies directed at TIGIT were initiated several years ago, but until recently little progress appeared to have been made. In March 2020, Roche launched a pivotal phase 3 trial (SKYSCRAPER-01; NCT04294810) evaluating tiragolumab (RG6058), a monoclonal antibody that binds to TIGIT, as frontline therapy for patients with locally advanced unresectable or metastatic non–small cell lung cancer (NSCLC) in combination with the PD-L1 inhibitor atezolizumab (Tecentriq).

Other pharmaceutical developers also joined the race. Most of the novel agents are being paired with immune checkpoint inhibitors (ICIs) in early-phase clinical studies, typically in combination with established and emerging PD-1/PD-L1 pathway ICIs (Table).

Table. TIGIT-Directed Agents in Clinical Development

The search for alternative immune checkpoints that may offer improved or complementary targets for immunotherapy is aimed at overcoming some of the challenges of ICIs. Despite the transformative success of ICIs in numerous cancer types over the past decade, a substantial proportion of patients do not respond, some immunologically “cold” tumor types are notoriously resistant, and many patients experience severe immunerelated adverse events (irAEs).^1,2

Although some high-profile disappointments have tempered enthusiasm for novel ICI targets,^3-5 the current spate of activity surrounding TIGIT shows that the hunt is still on. Studies combining TIGIT-directed antibodies with PD-1/PD-L1 pathway ICIs have become particularly attractive in light of data showing coexpression of TIGIT and PD-L1 across many types of cancer.^6-8

Several Mechanisms of Action

Activating and inhibitory receptors on the surface of immune cells, dubbed immune checkpoints, are essential for maintaining a delicate balance between immune response and tolerance. Best known are PD-1 and CTLA-4, coinhibitory receptors that transmit a secondary signal to T cells after antigen priming, which inhibits T-cell activation.^1,2

First described in 2009,9 TIGIT is an inhibitory receptor that competes with an activating receptor—in this case DNAM-1, also known as CD226, for binding to the same set of ligands; namely, CD155 and CD112. Regulation of TIGIT activity is made more complex, however, by the fact that it also binds to 2 additional ligands: CD113^6,7,10,11 and, most recently discovered, nectin-4 (Figure¹¹).¹²

Figure. TIGIT's Role in Suppressing Immune Reactions¹¹

These ligands and receptors belong to the nectin/nectin-like family of proteins, a subfamily within the broader immunoglobulin superfamily; CD155 is alternatively known as nectin-like 5; CD112, nectin-2, and CD113, nectin-3.

Many members of the family also serve as receptors for viruses, such as the poliovirus; hence, alternative nomenclature for CD155 is the poliovirus receptor (PVR), and CD112, CD113, and nectin-4 are otherwise referred to as PVRL2, PVRL3, and PVRL4, respectively.^6,7,10,11

Adding to the complexity, in addition to competing with DNAM-1, TIGIT also competes with 2 inhibitory receptors, CD96 (also known as TACTILE) and CD112R (or PVRIG for PVR related immunoglobulin domain containing) for binding to their respective ligands, CD155 and CD112. ^6,7,10,11

TIGIT’s predominant ligand is CD155 and, in a hierarchy of binding, it has the highest affinity for this ligand, followed by CD96 and then DNAM-1. Thus, the scale is weighted in favor of immune suppression when TIGIT is expressed.6,7,10,11

TIGIT is composed of an extracellular immunoglobulin variable domain, a transmembrane domain, and a short intracellular domain containing an immunoreceptor tyrosine- based inhibitory motif (ITIM). It is expressed predominantly on natural killer (NK) cells and T cells, major effectors of the immune response.^6,7,10,11 Upon ligand binding, TIGIT delivers an inhibitory signal into the cell via its ITIM and deactivates an array of downstream cellular proteins that dampen activating signals.^6,7,10,11

CD155 and CD112 are both overexpressed in a variety of human malignancies and CD155 expression is associated with poor prognosis. TIGIT also is upregulated on T and NK cells in a variety of cancer types, including NSCLC, melanoma, breast and colon cancers, and multiple myeloma.^6,7,10,11

Studies have shown that TIGIT downregulates the immune response via a number of potential mechanisms, acting at multiple steps in the cancer immunity cycle. In addition to directly inhibiting the activation of NK and T cells, TIGIT affects CD155-expressing cells, predominantly dendritic cells, preventing their maturation and triggering production of the immunosuppressive cytokine IL-10, which indirectly inhibits effector cell responses.^6,9,13,14

Another proposed mechanism of action of TIGIT in cancer immunity involves blocking DNAM-1 activity by outcompeting it for CD155 binding and by disrupting CD155 homodimerization. Finally, TIGIT is also expressed on regulatory T cells (Tregs) and has been shown to heighten their immunosuppressive function.^6,9,13,14

Early TIGIT Findings

Vibostolimab

For several years, a number of pharmaceutical companies have been developing antagonistic antibodies targeting TIGIT. At the 2018 Society for the Immunotherapy of Cancer (SITC) Annual Meeting, preliminary results were presented from phase 1 studies of vibostolimab (MK-7684) and etigilimab (OMP-313M32), both humanized TIGIT antibodies.^15,16

In a first-in-human study (NCT02964013), patients with metastatic, previously treated solid tumors were treated with escalating doses (2.1, 7, 21, 70, 210, and 700 mg q3w) of vibostolimab as monotherapy and combined with the PD-1 inhibitor pembrolizumab (Keytruda). Findings were reported for 34 patients treated with monotherapy and 43 who received the combination, which included 13 patients who crossed over from the monotherapy arm.

The overall response rate (ORR) with vibostolimab alone was 3%, including 1 partial response (PR) and 11 patients with stable disease (SD) for a disease control rate (DCR) of 35% (95% CI, 20%-54%). For the combination, the ORR was 19%, including 8 PRs and 12 SDs for a DCR of 47% (95% CI, 31%-62%).¹⁵

There were no dose-limiting toxicities (DLTs) and treatment-related adverse events (TRAEs) occurred in 53% (monotherapy) and 65% (combination therapy) of patients, which were grade 3 or higher in 6% and 12% of patients, respectively. The most common TRAEs were fatigue and pruritus in the monotherapy arm and pruritus and rash with combination therapy.¹⁵

Merck has started a phase 2 trial testing vibostolimab plus chemotherapy in patients with previously untreated NSCLC (NCT04165070) and has initiated several earlier-phase studies in melanoma and other advanced solid tumors.

Etigilimab

Etigilimab was evaluated as a single agent and in combination with the PD-1 antibody nivolumab (Opdivo) in patients with advanced or metastatic solid tumors in a phase 1a study (NCT03119428). Data from 18 patients treated with monotherapy doses ranging from 0.3 to 20.0 mg/kg every 2 weeks, in the doseescalation portion of the study, demonstrated best response of SD in 7 patients. The agent was well tolerated, with no DLTs, and common TRAEs included rash, fatigue, nausea, pruritus, and cough. Rash, pruritus, autoimmune hepatitis, and stomatitis were among the irAEs.¹⁶

The trial was terminated for undisclosed reasons, according to an update posted in August 2020 on ClinicalTrials.gov. However, Mereo BioPharma Group plc, which acquired etigilimab through a merger and has since secured worldwide development rights, plans to launch a phase 1b trial in solid tumors during 2020.¹⁷

Setting the Pace: Tiragolumab

Early clinical experience highlighted limited efficacy of TIGIT antibodies as monotherapy and ongoing trials focus on combinations, particularly in light of preclinical evidence of synergy with PD-1 inhibition.¹⁸

Tiragolumab (formerly called MTIG7192A) is a fully human monoclonal antibody that blocks the binding of TIGIT to its PVR and CD226 ligands; it has emerged as the current frontrunner.^19,20 In the first-in-human phase 1 GO30103 study (NCT02794571), the results of which were presented at the American Association for Cancer Research Virtual Annual Meeting II, tiragolumab was evaluated as monotherapy and in combination with atezolizumab in advanced solid cancers.

In the trial’s dose-escalation portion, 24 patients were treated with monotherapy and 49 with combination therapy. There were no objective responses with tiragolumab monotherapy, although 4 patients showed tumor reduction. With the combination, 10 patients showed tumor reduction, including 5 PRs. In an expansion cohort, 13 immunotherapy-naïve patients with PD-L1-positive NSCLC (≥ 1%) were treated with combination therapy. Six patients (46%) responded, including 2 who experienced a CR and 4 reaching PRs, for a DCR rate of 85%.²¹

Tiragolumab was well tolerated and had an acceptable safety profile across all doses studied. There were no DLTs, with just 4% grade 3 or higher TRAEs in both arms and no grade 5 events. The most common AEs included anemia, constipation, and fatigue. Overall, 17% of those who received tiragolumab monotherapy and 59% who had the combination experienced irAEs.²¹

Building upon these results, the phase 2 CITYSCAPE trial (GO40290; NCT03563716) was initiated to compare tiragolumab (600 mg q3w) plus atezolizumab with atezolizumab plus placebo in patients with newly diagnosed, PD-L1-positive (tumor proportion score [TPS] ≥ 1% of tumor cells) NSCLC, without EGFR or ALK alterations.¹⁹

In an updated analysis, both ORR and median PFS were improved in the tiragolumab arm, according to findings presented at the 2020 American Society for Clinical Oncology Virtual Scientific Program. Over a median follow-up of 10.9 months, the ORR in the intention-to-treat population (N = 135) was 37% in the tiragolumab arm compared with 21% with atezolizumab alone. The median PFS was 5.55 months (95% CI, 4.21-10.4) versus 3.88 months (95% CI, 2.73-4.53), for a stratified HR favoring the combination of 0.58 (95% CI, 0.38-0.89).¹⁹

In an exploratory analysis, the ORR in the cohort of patients (n = 58) with high PD-L1 expression (TPS ≥ 50%) was 66% for the tiragolumab combination versus 24% with atezolizumab alone. The median PFS was not reached (NR) for the combination (95% CI, 5.49 months-NR) compared with 4.11 months (95% CI, 2.07-4.73) for atezolizumab (unstratified HR, 0.30; 95% CI, 0.15-0.61).¹⁹

The combination was well tolerated, with similar rates of overall and grade 3 or higher any-cause AEs in the 2 arms. The incidence of irAEs was higher with the combination, although these primarily involved rash and infusion-related reactions and were of grade 1 or 2 severity.¹⁹

Roche has launched an extensive development program involving tiragolumab, including pivotal phase 3 clinical trials in NSCLC (SKYSCRAPER-01; NCT04294810) and extensive-stage small cell lung cancer (SKYSCRAPER-02; NCT04256421).

References:

1. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1-11. doi:10.1038/s12276-018-0191-1
2. Wilky BA. Immune checkpoint inhibitors: the linchpins of modern immunotherapy. Immunol Rev. 2019;290(1):6-23. doi:10.1111/imr.12766
3. Mazzarella L, Duso BA, Trapani D, et al. The evolving landscape of ‘next-generation’ immune checkpoint inhibitors: a review. Eur J Cancer. 2019;117:14-31. doi:10.1016/j.ejca.2019.04.035
4. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155. doi:10.1186/s12943-019-1091-2
5. Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083-1097. doi:10.1016/S1470-2045(19)30274-8
6. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200(2):108-119. doi:10.1111/cei.13407
7. Solomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother. 2018;67(11):1659-1667. doi:10.1007/s00262-018-2246-5
8. Anderson AE, Lopez A, Udyavar N , et al. Characterization of AB154, a humanized, non-depleting α-TIGIT antibody undergoing clinical evaluation in subjects with advanced solid tumors. Poster presented at: 34th Annual Meeting of the Society for the Immunotherapy of Cancer; November 7-10, 2019; National Harbor, MD. Accessed August 7, 2020. https://www.arcusbio.com/static/media/2019-SITC-AB154-Presented.0b34688e.pdf 
9. Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48-57. doi:10.1038/ni.1674
10. Sanchez-Correa B, Valhondo I, Hassouneh F, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE axis: novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers (Basel). 2019;11(6):877. doi:10.3390/cancers11060877
11. Gorvel L, Olive D. Targeting the “PVR-TIGIT axis” with immune checkpoint therapies. F1000Res. 2020;9:F1000 Faculty Rev-354. doi:10.12688/f1000research.22877.1
12. Reches A, Ophir Y, Stein N, et al. Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. J Immunother Cancer. 2020;8(1):e000266. doi:10.1136/jitc-2019-000266
13. Kurtulus S, Sakuishi K, Ngiow SF, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 125(11):4053-4062. doi:10.1172/JCI81187
14. Manieri NA, Chiang EY, Grogan JL. TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol. 2017;38(1):20-28. doi:10.1016/j.it.2016.10.002
15. Golan T, Bauer T, Jimeno A, et al. Phase 1 dose-finding study of the anti-TIGIT antibody MK-7684 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Presented at: 33rd Annual Meeting of the Society for the Immunotherapy of Cancer; November 7-11, 2018; Washington, DC. 
16. Sharma S, Moore K, Mettu N, et al. Initial results from a phase 1a/b study of etigilimab (OMP-313M32), an anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody, in advanced solid tumors. Poster presented at the 33rd Annual Meeting of the Society for the Immunotherapy of Cancer; November 7-11, 2018; Washington, DC.
17. Financial results for the year ended December 31, 2019. Mereo BioPharma Group plc. June 16, 2020. Accessed August 30, 2020. https://www.mereobiopharma.com/media/1467/mereo-biopharma-prelims-results_16-june-2020-final.pdf
18. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell. 2014;26(6):923-937. doi:10.1016/j.ccell.2014.10.018
19. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503
20. Plieth J. Roche move endorses Iteos’s Tigit widget. Evaluate. Published March 3, 2020. Accessed August 3, 2020. https://bit.ly/3lErSJg
21. Bendell JC, Bedard PL, Bang YJ, et al. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Paper presented: American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020. Accessed August 7, 2020. https://cancerres.aacrjournals.org/content/80/16_Supplement/CT302.abstract