TIGIT
| TIGIT | |||
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Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
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| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
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| Location (UCSC) | Chr 3: 114.28 – 114.31 Mb | Chr 16: 43.47 – 43.48 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
TIGIT (
Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients.[9] Mechanistically, research has shown that TIGIT-Fc fusion protein could interact with PVR on dendritic cells and increase its IL-10 secretion level/decrease its IL-12 secretion level under LPS stimulation, and also inhibit T cell activation in vivo.[6] TIGIT's inhibition of NK cytotoxicity can be blocked by antibodies against its interaction with PVR and the activity is directed through its ITIM domain.[10]
Clinical significance
TIGIT regulates
HIV
During Human Immunodeficiency Virus (
Cancer
TIGIT and
- 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]
See also
- T cell receptor
- Antigen
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000181847 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000071552 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Lung Cancer and Immunotherapy with Dr. Patrick Forde and Oswald Peterson". YouTube. October 22, 2021. Retrieved 5 July 2022.
- ^ S2CID 205361984.
- PMID 19197944.
- PMID 21416464.
- PMID 34367161.
- PMID 19815499.
- ^ a b Pharmaceutical Leaders Highlight Promise of TIGIT. Feb 2017
- ^ PMID 26741490.
- S2CID 205073070.
- ^ PMID 25866972.
- PMID 25465800.
- S2CID 245059452.
- ^ Adams B (2021-11-10). "Roche posts 'impressive' TIGIT combo lung cancer data, but trial deaths weigh down shares". Fierce Pharma. Retrieved 2023-10-13.
- ^ "Looking beyond Roche's Tigit bombshell". Evaluate.com. 2022-05-11. Retrieved 2024-01-20.
- ^ "[Ad hoc announcement pursuant to Art. 53 LR] Roche reports interim results for phase III SKYSCRAPER-01 study in PD-L1-high metastatic non-small cell lung cancer". www.roche.com (Press release). Retrieved 2023-10-12.
- ^ "Another twist in the TIGIT saga". ApexOnco. Retrieved 2023-10-12.
- ^ "[Ad hoc announcement pursuant to Art. 53 LR] Roche provides update on Phase III Skyscraper-01 study in PD-L1-high metastatic non-small cell lung cancer". www.roche.com (Press release). Retrieved 2023-10-12.
- S2CID 259083998.
- ISSN 0732-183X.
- ^ Salani R (2023-11-05). "Efficacy and safety results from SKYSCRAPER-04: An open-label randomized phase 2 trial of tiragolumab plus atezolizumab for PD-L1-positive recurrent cervical cancer". medically.roche.com. Retrieved 2024-01-20.
- ^ Hsu CH (2024-01-18). "SKYSCRAPER-08: a phase III, randomized, double-blind, placebo-controlled study of first-line tiragolumab + atezolizumab and chemotherapy in patients with esophageal squamous cell carcinoma". medically.roche.com. Retrieved 2024-01-20.
- ^ Sun JM (2024-01-18). "MORPHEUS-EC: a phase Ib/II open-label, randomized study of tiragolumab plus atezolizumab plus chemotherapy in patients with previously untreated locally advanced unresectable or metastatic esophageal cancer". medically.roche.com. Retrieved 2024-01-20.
Further reading
- Riquelme P, Haarer J, Kammler A, Walter L, Tomiuk S, Ahrens N, Wege AK, Goecze I, Zecher D, Banas B, Spang R, Fändrich F, Lutz MB, Sawitzki B, Schlitt HJ, Ochando J, Geissler EK, Hutchinson JA (2018). "TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity". Nature Communications. 9 (2858): 2858. PMID 30030423.