A Hybrid Multiscale Model for Predicting CAR-T Therapy Outcomes in Solid Tumors

Area of Science:

• Immunology
• Biomedical Engineering
• Computational Biology

Background:

• CAR-T cell therapy success hinges on T cell infiltration into tumors, termed 'tumor hotness'.
• Limited understanding of T cell-tumor microenvironment interactions hinders immunotherapy progress.
• Existing strategies for enhancing T cell accumulation face challenges due to complex microenvironmental barriers.

Purpose of the Study:

• To develop a physiological mechanistic model of the 3D tumor microenvironment (TME).
• To evaluate CAR-T cell performance under varying environmental conditions and infusion strategies.
• To identify key barriers limiting CAR-T cell efficacy and inform optimization strategies.

Main Methods:

• Developed a 3D mechanistic model integrating vascular (rolling, adhesion, endothelial suppression) and interstitial (ECM density, metabolic competition, chemokine sensitivity) barriers.
• Simulated CAR-T cell distribution and performance within the TME under different conditions.
• Quantitatively analyzed the impact of specific microenvironmental factors on CAR-T cell infiltration and efficacy.

Main Results:

• Collagen density and metabolic competition were identified as dominant factors limiting CAR-T cell efficacy.
• Enhanced vascular adhesion improved infiltration but was ultimately constrained by collagen and metabolism.
• Endothelial suppression significantly reduced tumor hotness; its alleviation improved response.
• Systemic infusion resulted in higher tumor hotness than intratumoral delivery, with combined routes or reduced collagen restoring efficacy in dense tumors.

Conclusions:

• The developed mechanistic framework enables a quantitative understanding of CAR-T cell-TME interactions.
• Stromal and metabolic constraints are more critical than vascular adhesion for CAR-T cell efficacy.
• This model provides a foundation for rational optimization of CAR-T cell design and delivery strategies to overcome resistance in solid tumors.