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Quantitative systems pharmacology modeling of macrophage-targeted therapy combined with PD-L1 inhibition in advanced
Hanwen Wang1, Theinmozhi Arulraj1, Samira Anbari1
1Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Immune checkpoint inhibitors remained the standard-of-care treatment for advanced non-small cell lung cancer (NSCLC) for the past decade. In unselected patients, anti-PD-(L)1 monotherapy achieved an overall response rate of about 20%. In this analysis, we developed a pharmacokinetic and pharmacodynamic module for our previously calibrated quantitative systems pharmacology model (QSP) to simulate the effectiveness of macrophage-targeted therapies in combination with PD-L1 inhibition in advanced NSCLC. By conducting in silico clinical trials, the model confirmed that anti-CD47 treatment is not an optimal option of second- and later-line treatment for advanced NSCLC resistant to PD-(L)1 blockade. Furthermore, the model predicted that inhibition of macrophage recruitment, such as using CCR2 inhibitors, can potentially improve tumor size reduction when combined with anti-PD-(L)1 therapy, especially in patients who are likely to respond to anti-PD-(L)1 monotherapy and those with a high level of tumor-associated macrophages. Here, we demonstrate the application of the QSP platform on predicting the effectiveness of novel drug combinations involving immune checkpoint inhibitors based on preclinical or early-stage clinical trial data.
Insights
Quantitative systems pharmacology modeling suggests combining CCR2 inhibitors with anti-PD-(L)1 therapy may improve outcomes in advanced non-small cell lung cancer (NSCLC), unlike anti-CD47. This approach shows promise for patients resistant to PD-(L)1 blockade.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors, particularly anti-PD-(L)1, have been standard for advanced non-small cell lung cancer (NSCLC), with ~20% response rates in unselected patients.
- Developing novel combination therapies is crucial to overcome resistance and improve treatment efficacy in advanced NSCLC.
Purpose of the Study:
- To develop and apply a quantitative systems pharmacology (QSP) model to predict the efficacy of macrophage-targeted therapies combined with PD-L1 inhibition in advanced NSCLC.
- To evaluate anti-CD47 and CCR2 inhibition as combination strategies with anti-PD-(L)1 therapy in silico.
Main Methods:
- Developed a pharmacokinetic/pharmacodynamic module integrated into a pre-existing QSP model.
- Conducted in silico clinical trials to simulate treatment responses in advanced NSCLC models.
- Assessed combination therapies including anti-PD-(L)1 with anti-CD47 or CCR2 inhibitors.
Main Results:
- In silico trials indicated anti-CD47 is suboptimal for second- or later-line treatment in PD-(L)1-resistant advanced NSCLC.
- Predicted that inhibiting macrophage recruitment (e.g., CCR2 inhibitors) combined with anti-PD-(L)1 therapy could enhance tumor reduction.
- Identified patient subgroups (responders to anti-PD-(L)1 monotherapy, high tumor-associated macrophages) likely to benefit from CCR2 inhibition combinations.
Conclusions:
- The QSP platform effectively predicts novel drug combination efficacy in advanced NSCLC.
- CCR2 inhibition combined with anti-PD-(L)1 therapy shows potential for improving treatment outcomes, particularly in specific patient populations.
- Anti-CD47 is not recommended as a subsequent line of therapy in this context.
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