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Background <p>Finding effective and curative treatment for mesothelioma remains challenging. While the introduction of immunotherapy combinations using ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have offered hope for some patients, a large proportion of mesothelioma cases, particularly the epithelial subtype, have minimal benefit from this.</p> Methods <p>Our study was inspired by the results of the AdvanTG-105 phase I clinical trial, which showed partial response with anti-TIGIT/PD-1 treatment in two epithelioid mesothelioma patients. Here, we conducted a comprehensive in vivo experiment involving eight animal treatment groups administered with either PBS (control group), cisplatin/pemetrexed, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-TIGIT, anti-PD-1 + anti-TIGIT, anti-PD-1 + anti-CTLA-4 + anti-TIGIT, and cisplatin/pemetrexed + anti-PD-1 + anti-TIGIT.</p> Results <p>Our results indicate that animals receiving anti-PD-1 + TIGIT exhibited a superior anti-tumour response, with 90% of the treatment group exhibiting an objective response, compared to 60%, 20% and 40% for the standard-of-care anti-PD-1 + CTLA-4, single-agent anti-PD-1 and cisplatin/pemetrexed treatment groups, respectively. Animals receiving anti-PD-1 + TIGIT displayed a significantly reduced average tumour size, with improved weight and survival rates, and fewer adverse effects than those receiving anti-PD-1 + CTLA-4 treatment. Anti-PD-1 + TIGIT-treated animals achieved complete tumour regression, with heightened effector CD8 + T cell and NK cell activity, remaining tumour-free for over 300&#xa0;days without immune-related adverse events. After initial tumour elimination, anti-PD-1 + TIGIT-treated animals showed no tumour regrowth in the rechallenge experiment.</p> Conclusion <p>These findings provide rationale for the development of an anti-PD-1 + TIGIT combination immunotherapy trial for mesothelioma patients.</p> Graphical Abstract <p>Top) The comparison of standard-of-care treatment and anti-TIGIT novel combination treatment in the mesothelioma animal models, with an example of response treated with tislelizumab and ociperlimab in a pleural mesothelioma patient in the AdvanTIG-105 study. The number of animals/patients treated and the number of treatment responders are presented. Bottom) Schematic illustration of anti-tumour immune response at the cellular level induced by anti-PD-1/TIGIT checkpoint blockade for efficient cancer immunotherapy.</p> <p></p>

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A combination of PD-1 and TIGIT immune checkpoint inhibitors elicits a strong anti-tumour response in mesothelioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月12日

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  • Huaikai Shi,
  • Ta-Kun Yu,
  • Ben Johnson,
  • Sakthi Priya Selvamani,
  • Ling Zhuang,
  • Kenneth Lee,
  • Sonja Klebe,
  • Samuel Smith,
  • Kirby Wong,
  • Kate Chen,
  • Georgina Clark,
  • Emma M. Rath,
  • Holly Pearson,
  • David Gallego Ortega,
  • Anthony Linton,
  • Steven Kao,
  • Pablo Silveira,
  • Yuen Yee Cheng

摘要

Background

Finding effective and curative treatment for mesothelioma remains challenging. While the introduction of immunotherapy combinations using ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have offered hope for some patients, a large proportion of mesothelioma cases, particularly the epithelial subtype, have minimal benefit from this.

Methods

Our study was inspired by the results of the AdvanTG-105 phase I clinical trial, which showed partial response with anti-TIGIT/PD-1 treatment in two epithelioid mesothelioma patients. Here, we conducted a comprehensive in vivo experiment involving eight animal treatment groups administered with either PBS (control group), cisplatin/pemetrexed, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-TIGIT, anti-PD-1 + anti-TIGIT, anti-PD-1 + anti-CTLA-4 + anti-TIGIT, and cisplatin/pemetrexed + anti-PD-1 + anti-TIGIT.

Results

Our results indicate that animals receiving anti-PD-1 + TIGIT exhibited a superior anti-tumour response, with 90% of the treatment group exhibiting an objective response, compared to 60%, 20% and 40% for the standard-of-care anti-PD-1 + CTLA-4, single-agent anti-PD-1 and cisplatin/pemetrexed treatment groups, respectively. Animals receiving anti-PD-1 + TIGIT displayed a significantly reduced average tumour size, with improved weight and survival rates, and fewer adverse effects than those receiving anti-PD-1 + CTLA-4 treatment. Anti-PD-1 + TIGIT-treated animals achieved complete tumour regression, with heightened effector CD8 + T cell and NK cell activity, remaining tumour-free for over 300 days without immune-related adverse events. After initial tumour elimination, anti-PD-1 + TIGIT-treated animals showed no tumour regrowth in the rechallenge experiment.

Conclusion

These findings provide rationale for the development of an anti-PD-1 + TIGIT combination immunotherapy trial for mesothelioma patients.

Graphical Abstract

Top) The comparison of standard-of-care treatment and anti-TIGIT novel combination treatment in the mesothelioma animal models, with an example of response treated with tislelizumab and ociperlimab in a pleural mesothelioma patient in the AdvanTIG-105 study. The number of animals/patients treated and the number of treatment responders are presented. Bottom) Schematic illustration of anti-tumour immune response at the cellular level induced by anti-PD-1/TIGIT checkpoint blockade for efficient cancer immunotherapy.