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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with
Huafeng Wei1, Likun Zhao2, Wei Li1
1International Joint Cancer Institute, Second Military Medical University, Shanghai, China ; School of Pharmacy, Liaocheng University, Liaocheng, China.
Abstract:
There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 × 10(6) ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8(+) T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-γ production. While administration of anti-CD137 mAb as a single agent similarly increases CD8(+) T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical 'translation'.
Insights
Combining anti-CD137 and anti-PD-1 monoclonal antibodies (mAbs) with cisplatin significantly improves survival in ovarian cancer models. This combination therapy enhances CD8(+) T cell responses, suggesting potential for clinical translation in advanced ovarian carcinoma.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Advanced ovarian carcinoma requires improved therapeutic strategies.
- Immune-modulatory monoclonal antibodies (mAbs) can generate anti-tumor immune responses.
- Previous research indicated potential for combined mAb therapy.
Purpose of the Study:
- To investigate the therapeutic efficacy of various mAb combinations in a mouse ovarian cancer model.
- To evaluate the impact of adding cisplatin to mAb combinations.
- To explore the underlying immunological mechanisms of effective treatments.
Main Methods:
- Utilized the ID8 mouse ovarian cancer model with established intraperitoneal tumors.
- Administered various combinations of monoclonal antibodies (mAbs), including anti-CD137 and anti-PD-1, and cisplatin.
- Assessed overall survival, T cell populations (CD8+), T cell functionality (cytolytic activity, IFN-γ production), and immunological memory.
Main Results:
- A combination of anti-CD137 and anti-PD-1 mAbs doubled overall survival in ovarian cancer models.
- This mAb combination increased functional CD8(+) T cells in peritoneal lavage and spleens.
- Adding cisplatin to the anti-CD137/anti-PD-1 mAb combination resulted in survival exceeding 90 days, potentially curative, and showed efficacy in lung tumors.
Conclusions:
- The combination of anti-CD137 and anti-PD-1 mAbs, particularly with cisplatin, demonstrates significant therapeutic potential for advanced ovarian carcinoma.
- This combination therapy enhances systemic, tumor-specific CD8(+) T cell responses and induces immunological memory.
- The findings support clinical translation of this multi-agent approach for treating ovarian and potentially other cancers.
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