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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Resistance to PD1/PDL1 checkpoint inhibition
Jake S O'Donnell1, Georgina V Long2, Richard A Scolyer3
1Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia; School of Medicine, The University of Queensland, Herston 4006, Queensland, Australia; Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia.
Abstract:
For the first time in decades, patients with difficult-to-treat cancers such as advanced stage metastatic melanoma are being offered a glimpse of hope in the form of immunotherapies. By targeting factors that foster the development and maintenance of an immunosuppressive microenvironment within tumors, these therapies release the brakes on the host's own immune system; allowing cure of disease. Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ∼70%, and overall survival (>5years) to ∼30%. Despite this unprecedented efficacy, many patients fail to respond, and more concerning, some patients who demonstrate encouraging initial responses to immunotherapy, can acquire resistance over time. There is now an urgent need to identify mechanisms of resistance, to predict outcome and to identify targets for combination therapy. Here, with the aim of guiding future combination trials that target specific resistance mechanisms to immunotherapies, we have summarised and discussed the current understanding of mechanisms promoting resistance to anti-PD1/PDL1 therapies, and how combination strategies which target these pathways might yield better outcomes for patients.
Insights
Immunotherapies offer new hope for advanced melanoma by harnessing the immune system. Understanding and targeting resistance mechanisms is crucial for improving patient outcomes and developing effective combination therapies.
Area of Science:
- Oncology
- Immunology
- Cancer Therapy
Background:
- Immunotherapies, including ipilimumab and pembrolizumab, have significantly improved survival rates for advanced melanoma patients.
- These therapies work by targeting immune checkpoints like CTLA4 and PD-1, releasing the host immune system to fight cancer.
- Despite successes, many patients do not respond, and some develop resistance over time.
Purpose of the Study:
- To review and discuss current knowledge on mechanisms of resistance to anti-PD1/PDL1 immunotherapies.
- To guide the development of future combination therapies targeting specific resistance pathways.
- To improve treatment strategies for patients with difficult-to-treat cancers.
Main Methods:
- Literature review and synthesis of existing research on immunotherapy resistance mechanisms.
- Analysis of clinical trial data regarding response and resistance to PD-1/PDL1 inhibitors.
- Discussion of potential combination strategies based on identified resistance pathways.
Main Results:
- Significant improvements in three-year (∼70%) and five-year (>30%) survival rates for melanoma patients treated with immunotherapies.
- Identification of patient populations that fail to respond to current immunotherapies.
- Recognition of acquired resistance as a significant clinical challenge.
Conclusions:
- Understanding resistance mechanisms is critical for optimizing immunotherapy efficacy.
- Combination strategies targeting specific resistance pathways hold promise for better patient outcomes.
- Further research is needed to predict response and overcome resistance to immunotherapies.
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