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Antiangiogenic therapy enhances CAR-T cell efficacy in solid tumors: Insights from a hybrid multiscale model
Sayyed Mohammad Ali Mortazavi1, Bahar Firoozabadi1
1Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.
Background And Objectives:
Despite the remarkable success of chimeric antigen receptor (CAR) T cells in hematological malignancies, their therapeutic efficacy in solid tumors is still limited, largely due to the insufficient infiltration of CAR-T cells and the immunosuppressive tumor microenvironment (TME). Recently, murine studies have shown that anti-angiogenic therapy can improve the efficacy of CAR-T cells. However, extensive research is required to unveil the underlying mechanism and develop effective therapeutic protocols.
Methods:
Here, we developed a hybrid discrete - continuous multi-scale computational model to study solid tumor growth, angiogenesis, and CAR-T cell infiltration. Our model considers the intravenous infusion of CAR-T cells, their extravasation through the endothelium, and their cytotoxic effect in the TME. Therefore, this model enables us to robustly investigate the impact of anti-angiogenic therapy on the efficacy of CAR-T cells.
Results:
Our findings showed that anti-angiogenic therapy enhances the delivery and efficacy of CAR-T cells in solid tumors. Subsequently, we evaluated different therapeutic regimens. The results revealed that although both adjuvant and neoadjuvant anti-angiogenic therapy can improve outcome, the neoadjuvant regimen yields higher survival rates. Moreover, our model suggested an optimal dosing schedule to maximize survival.
Conclusions:
Our results provide profound insight into the therapeutic dynamics of combined anti-angiogenic and CAR-T cell therapy. Additionally, the model establishes a computational framework for selecting treatment regimens for clinical trials.
Insights
Anti-angiogenic therapy improves chimeric antigen receptor (CAR) T cell delivery and efficacy in solid tumors. A computational model suggests neoadjuvant anti-angiogenic therapy offers higher survival rates than adjuvant therapy.
Area of Science:
- Immunotherapy
- Computational Biology
- Oncology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows success in blood cancers but faces challenges in solid tumors due to poor infiltration and immunosuppressive tumor microenvironments (TMEs).
- Preclinical studies suggest anti-angiogenic therapy may enhance CAR T cell efficacy, but mechanisms and optimal protocols require further investigation.
Purpose of the Study:
- To investigate the impact of anti-angiogenic therapy on CAR T cell infiltration and efficacy in solid tumors using a multi-scale computational model.
- To evaluate different therapeutic regimens and identify optimal treatment strategies for combined anti-angiogenic and CAR T cell therapy.
Main Methods:
- Development of a hybrid discrete-continuous multi-scale computational model simulating solid tumor growth, angiogenesis, and CAR T cell dynamics.
- The model incorporates CAR T cell infusion, extravasation, and cytotoxic effects within the TME to assess anti-angiogenic therapy's impact.
Main Results:
- Anti-angiogenic therapy was found to significantly enhance CAR T cell delivery and overall efficacy in solid tumors.
- Both neoadjuvant and adjuvant anti-angiogenic therapy improved outcomes, with neoadjuvant regimens demonstrating higher survival rates.
- An optimal dosing schedule was identified through modeling to maximize patient survival.
Conclusions:
- The study provides critical insights into the therapeutic dynamics of combining anti-angiogenic and CAR T cell therapies.
- The developed computational model offers a framework for designing and selecting treatment regimens for future clinical trials in solid tumor immunotherapy.
Related Concept Videos
01:27Tumor Immunotherapy
01:10Mechanism of Angiogenesis