Engagement of PD-1 and TIGIT receptors.

When the TIGIT and PD-1 receptors engage with their respective ligands on cancer cells, they can drive down T cell activity, negatively impacting the body’s antitumor immune response. Exploring these pathways together could be a new way forward in GC/GEJC/EAC.1,2

Therapeutic opportunities

With low 5-year survival rates, opportunities to explore effective oncology options are needed for treating patients with HER2-negative metastatic GC/GEJC/EAC3-6

EXPLORE FURTHER

Dual pathway potential

Emerging evidence suggests exploring the TIGIT and PD-1 immune checkpoint pathways together may drive new potential in GC/GEJC/EAC1

LET'S GO

Evidence suggests opportunities for advancement in GC/GEJC/EAC

Most esophageal cancers are characterized as adenocarcinomas in the United States7

GEJC is often included as part of gastric and/or esophageal cancer studies8

Up to 95% of gastric cancers are adenocarcinomas9

Many patients are currently either unable to achieve a durable response or likely to relapse10

As the clinical landscape continues to progress for HER2-negative metastatic GC/GEJC/EAC, there may be opportunities for advancement beyond anti-PD-1 + chemotherapy1,11

PD-1 inhibitors have shown efficacy in patients with PD-L1+ GC/GEJC/EAC8

Statistics for patients with GC/GEJC/EAC

Currently available anti-PD-1 + chemotherapy regimens result in median OS of ~13-15 months and median PFS of ~7-8 months8,11,18

Illuminating potential for HER2-negative metastatic GC/GEJC/EAC through 2 pathways1,8,19,20

TIGIT and PD-1 are among the immune checkpoints often distinctly co-expressed on activated immune cells. While PD-1 pathway activation and its associated downstream effects on immune response have been well studied in GC/GEJC/EAC, there may be opportunity for further impact. Preclinical data indicate that combined inhibition of the TIGIT and PD-1 pathways may improve T cell proliferation and may increase cytokine secretion to enhance T cell activity, potentially addressing the body’s downregulated antitumor response.

Exploring the TIGIT and PD-1 pathways together may offer a novel path forward for new possibilities in HER2-negative metastatic GC/GEJC/EAC

TIGIT + PD-1 pathway.

Adapted from Banta et al. Immunity. 2022.

https://creativecommons.org/licenses/by/4.0/

Emerging immune checkpoint pathway potential

TIGIT is expressed on activated natural killer cells and T cells, including CD4+, CD8+, and regulatory T cells. Immune checkpoint receptors, like TIGIT, on T cells are necessary to limit T cell responses and prevent chronic T cell activation.1,21

There are multiple ways the TIGIT pathway can potentially suppress antitumor immune responses, including:

  • Directly inhibiting natural killer cell cytotoxic function1
  • Preventing activation of the costimulatory receptor CD226, a positive regulator of T cell responses21
  • Increasing suppressive function of regulatory T cells1
  • Inducing tolerogenic dendritic cells that can impair T cell proliferation and inhibit IFN-y production21

Research indicates the TIGIT pathway plays a critical role in antitumor immune responses.

PD-1 immune checkpoint pathway potential22,23

PD-1 has been well studied and found to be highly expressed on T cells in the tumor microenvironment. When PD-1 binds to PD-L1, T cell activity and antitumor immune responses are downregulated. Approaches that interrupt binding of PD-1 to PD-L1 have been used clinically for several types of cancers, including HER2-negative metastatic GC/GEJC/EAC.

Other immune checkpoints in GC/GEJC/EAC22-24

In addition to TIGIT and PD-1, CTLA-4 and LAG-3 are among other immune checkpoints that play a role in GC/GEJC/EAC.

Immune checkpoints in GC/GEJC/EAC.

CTLA-4 is an immune checkpoint expressed on activated T cells and immunosuppressive regulatory T cells. When CTLA-4 binds to the B7 ligand, expansion of activated T cells is reduced.

LAG-3 is expressed on activated T cells and can enhance the suppressive function of regulatory T cells when bound to one of its ligands. High expression of the LAG-3 immune checkpoint is associated with poor prognosis in several tumor types.

Simultaneous disruption of either CTLA-4 or LAG-3 and other immune checkpoint pathways in the tumor micro-environment has also been shown to support antitumor activity.

Immune checkpoints in GC/GEJC/EAC.

Find this information appealing? Get a printable PDF.

DOWNLOAD NOW

At Gilead, we’re committed to making an impact for those with GC/GEJC/EAC

EAC=esophageal adenocarcinoma; GC=gastric cancer; GEJC=gastroesophageal junction cancer; HER2=human epidermal growth factor receptor 2; OS=overall survival; PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PFS=progression-free survival; TIGIT=T cell immunoglobulin and ITIM domain.

References:
  1. Wang D, Gu Y, Yan X, et al. Role of CD155/TIGIT in digestive cancers: promising cancer target for immunotherapy. Front Oncol. 2022;12:844260.
  2. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034.
  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
  4. Janjigian YY, Moehler MH, Ajani JA, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649. Accessed February 28, 2025. https://ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.398
  5. American Cancer Society. Stomach Cancer Early Detection, Diagnosis, and Staging. Updated January 16, 2025. Accessed February 28, 2025. https://www.cancer.org/cancer/types/stomach-cancer/detection-diagnosis-staging/survival-rates.html
  6. American Cancer Society. Esophagus Cancer Early Detection, Diagnosis, and Stag. Updated January 16, 2025. Accessed February 28, 2025. https://www.cancer.org/cancer/types/esophagus-cancer/detection-diagnosis-staging/survival-rates.html
  7. Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol. 2012;23(12):3155-3162.
  8. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
  9. National Cancer Institute. Gastric Cancer Treatment (PDQ®) — Health Professional Version. Updated January 26, 2024. Accessed January 2025. https://www.cancer.gov/types/stomach/hp/stomach-treatment-pdq#_1
  10. Janjigian YY, Ajani JA, Moehler M, et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 Trial. J Clin Oncol. 2024;42(17):2012-2020.
  11. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024;385:e078876.
  12. Then EO, Lopez M, Saleem S, et al. Esophageal cancer: an updated surveillance epidemiology and end results database analysis. World J Oncol. 2020;11(2):55-64.
  13. Mamdani H, Jalal SI. Where to start and what to do next: the sequencing of treatments in metastatic esophagogastric cancer. Am Soc Clin Oncol Educ Book. 2021;41:1-16.
  14. National Cancer Institute: SEER 22. Cancer Stat Facts: Esophageal Cancer. Accessed March 3, 2025. https://seer.cancer.gov/statfacts/html/esoph.html
  15. National Cancer Institute: SEER 22. Cancer Stat Facts: Stomach Cancer. Accessed March 3, 2025. https://seer.cancer.gov/statfacts/html/stomach.html
  16. Gunturu KS, Woo Y, Beaubier N, Remotti HE, Saif MW. Gastric cancer and trastuzumab: first biologic therapy in gastric cancer. Ther Adv Med Oncol. 2013;5(2):143-151.
  17. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol. 2012;23(10):2656-2662.
  18. Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(11)1181-1195. Published correction appears in Lancet Oncol. 2024;25(12):e626.
  19. Banta KL, Xu X, Chitre AS, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022;55(3):512-526.e9. doi.org/10.1016/j.immuni.2022.02.005
  20. Nutsch K, Banta KL, Wu TD, et al. TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation Nat Cancer. 2024;5(12):1834-1851.
  21. Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338-1342.
  22. Sharma P, Goswami S, Raychaudhuri D, et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023;186(8):1652-1669.
  23. Sharma P, Goswami S, Raychaudhuri D, et al. Immune checkpoint therapy-current perspectives and future directions—Supplemental. Cell. 2023;186(8)(suppl):1652-1669.
  24. Li R, Qiu J, Zhang Z, et al. Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis. Cancer Cell Int. 2023;23(1):306.
  25. Cai X, Zhan H, Ye Y, et al. Current progress and future perspectives of immune checkpoint in cancer and infectious diseases. Front Genet. 2021;12:785153.
  26. Huo JL, Wang YT, Fu WJ, Lu N, Liu ZS. The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Front Immunol. 2022;13:956090.
TOP

This site is intended for US
healthcare professionals

PROCEED TO SITE

You are now leaving this site

Stay on site Continue