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Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies
Hongxing Shen1,2, Eddy Shih-Hsin Yang1,2, Marty Conry2,3
1Department of Radiation Oncology, The University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.
Abstract:
Immune checkpoint blockade therapies (ICBs) are a prominent breakthrough in cancer immunotherapy in recent years (named the 2013 "Breakthrough of the Year" by the Science magazine). Thus far, FDA-approved ICBs primarily target immune checkpoints CTLA-4, PD-1, and PD-L1. Notwithstanding their impressive long-term therapeutic benefits, their efficacy is limited to a small subset of cancer patients. In addition, ICBs induce inadvertent immune-related adverse events (irAEs) and can be costly for long-term use. To overcome these limitations, two strategies are actively being pursued: identification of predictive biomarkers for clinical response to ICBs and multi-pronged combination therapies. Biomarkers will allow clinicians to practice a precision medicine approach in ICBs (biomarker-based patient selection) such as treating triple-negative breast cancer patients that exhibit PD-L1 staining of tumor-infiltrating immune cells in ≥1% of the tumor area with nanoparticle albumin-bound (nab)-paclitaxel plus anti-PD-L1 and treating patients of MSI-H or MMR deficient unresectable or metastatic solid tumors with pembrolizumab (anti-PD-1). Importantly, the insights gained from these biomarker studies can guide rational combinatorial strategies such as CDK4/6 inhibitor/fractionated radiotherapy/HDACi in conjunction with ICBs to maximize therapeutic benefits. Further, with the rapid technological advents (e.g., ATCT-Seq), we predict more reliable biomarkers will be identified, which in turn will inspire more promising combination therapies.
Insights
Immune checkpoint blockade therapies (ICBs) show promise in cancer treatment but have limitations. Identifying biomarkers and developing combination therapies can improve patient selection and treatment efficacy for better outcomes.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Immune checkpoint blockade therapies (ICBs) represent a significant advancement in cancer immunotherapy.
- Current FDA-approved ICBs target CTLA-4, PD-1, and PD-L1, offering long-term benefits but limited efficacy in a subset of patients.
- Challenges include patient selection, immune-related adverse events (irAEs), and high costs.
Purpose of the Study:
- To explore strategies for overcoming limitations of ICBs.
- To highlight the role of predictive biomarkers in precision medicine for ICBs.
- To discuss the potential of combination therapies to enhance ICB efficacy.
Main Methods:
- Review of current ICB landscape and challenges.
- Analysis of biomarker identification for patient stratification.
- Exploration of combinatorial strategies involving ICBs.
Main Results:
- Biomarker-based patient selection enables precision medicine approaches, exemplified by specific treatment protocols for triple-negative breast cancer and MSI-H/MMR-deficient solid tumors.
- Insights from biomarker studies can inform rational combination therapies, including agents like CDK4/6 inhibitors, radiotherapy, and HDAC inhibitors.
- Technological advancements like ATCT-Seq are expected to yield more reliable biomarkers.
Conclusions:
- Biomarker discovery and combination therapies are crucial for enhancing ICB efficacy and patient outcomes.
- Precision medicine approaches guided by biomarkers will improve the application of ICBs.
- Future advancements in biomarker technology will likely drive the development of more effective combination therapies.
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